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DNA testing for Down syndrome

DNA testing for Down syndrome. Dr Nerine Gregersen Division Human Genetics NHLS and Wits University. DOWN SYNDROME . Commonest genetic cause of intellectual disability worldwide All ethnic groups Increased risk with advancing maternal age Age 25 1/1350 Age 35 1/400 Age 40 1/100

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DNA testing for Down syndrome

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  1. DNA testing for Down syndrome Dr Nerine Gregersen Division Human Genetics NHLS and Wits University

  2. DOWN SYNDROME • Commonest genetic cause of intellectual disability worldwide • All ethnic groups • Increased risk with advancing maternal age • Age 25 1/1350 • Age 35 1/400 • Age 40 1/100 • Age 45 1/30

  3. Down syndrome • Birth prevalence • 1/700 births worldwide • 1/500 in RSA • Cause • Non-disjunction / trisomy 95% • Translocation 4% • About 50% de novo • Mosaicism 1%

  4. Photo used with parental consent

  5. Down syndrome clinical features • Craniofacial • Brachycephaly, upslanted eyes, epicanthic folds, flat facial profile, flat nasal bridge, (protruding tongue), (dysplastic ears) • Limbs • Brachydactyly, single palmar crease, clinodactyly, sandle-gap • Cardiac (40%) • ASD, VSD, AVSD, PDA • CNS • Hypotonia, developmental delay, MR • Other • GIT abn (~15%), short stature • Features common in normal black neonates • Features useful for diagnosis in black patients

  6. Down syndromecomplications • Atlanto-axial instability • Transient neonatal ‘leukaemia’ • ALL (20 X greater risk) • Hypothyroidism (antibodies) in 30% • Alzheimer disease • 8% by 49 yrs • 75% by 60yrs

  7. TESTING

  8. 100 base pairs 105 109 DNA sequencing FISH Chromosome banding CGH and MLPA

  9. CHROMOSOMES DNA Live, dividing cells Any tissue Screen all chromosomes Test specific regions TAT 2 – 4 weeks TAT 72 hours Labour intensive Can be automated

  10. Short tandem repeats (STR) • STR = microsatellite markers • 10 000’s across genome • Stretches of DNA of units of 2-4 nucleotides • TGTG…TG • CAACAA….CAA • Different alleles exist for each STR in popn. • Each allele differs in repeat length

  11. (CC)12 (CC)11 (CC)7 (CC)8 (AAC)26 (AAC)18 (AAC)10 (AAC)15 (CC)11 (CC)12 (CC)7 (CC)8 (AAC)26 (AAC)15 (AAC)18 (AAC)10

  12. Quantitative fluorescent PCR aneuploidy screen (QF-PCR) Principle: • Test STR markers on chromosomes • 4-5 on autosomes of choice (13, 18, 21) • Fewer on X and Y • Used to detect numerical chromosome abnormalities • Can test blood, amniotic fluid, CVS, post-mortem tissue etc.

  13. QF-PCR Advantages • Rapid result (48 – 72 hours) • 99% accuracy • No live cells required Disadvantages • Won’t detect mosaicism (<30%) • Won’t detect other chromosome abnormalities • Mechanism of aneuploidy remains unknown • Blood-stained amnio may make testing impossible • Risk of maternal contamination if CVS not carefully prepared/dissected

  14. Past … Pre-and postnatal testing for DS by karyotyping Postnatal testing for DS by karyotyping Prenatal testing for DS in AMA women by QF-PCR January 2007 – May 2008 563 requests for DS testing

  15. Past … Pre-and postnatal testing for DS by karyotyping Postnatal testing for DS by karyotyping Prenatal testing for DS in AMA women by QF-PCR January 2007 – May 2008 563 requests for DS testing 185 not DS (33%) 67 no result 4 other chromosome abnormalities 307 confirmed DS (54.5%) + 79 confirmed DS on specimens not requested as DS = 386 confirmed DS

  16. Past … Pre-and postnatal testing for DS by karyotyping Postnatal testing for DS by karyotyping Prenatal testing for DS in AMA women by QF-PCR January 2007 – May 2008 563 requests for DS testing 185 not DS (33%) 67 no result 4 other chromosome abnormalities 307 confirmed DS (54.5%) + 79 confirmed DS on specimens not requested as DS = 386 confirmed DS 366 trisomy 95% 6 mosaic 1.5% 14 translocation 3.5%

  17. …present Indication for DS testing Postnatal testing for DS by QF-PCR Prenatal testing for DS in AMA women by QF-PCR Confirmed DS ~2% RR relates to inherited translocation 98% RR relates to trisomy Offer parental karyotype

  18. …present Indication for DS testing Postnatal testing for DS by QF-PCR Prenatal testing for DS in AMA women by QF-PCR Negative QF-PCR Confirmed DS ~2% RR relates to inherited translocation Dysmorphic features Unknown diagnosis 98% RR relates to trisomy Strongly suspect DS ?mosaic Request karyotype Genetic counselling Refer to Genetics Offer prenatal testingand/or parental karyotypeif recurrence risk perceived as high

  19. Baby with multiple congenital abnormalities Alive Stillborn Macerated Skin snip (saline) QF-PCR T13, 18, 21, X, Y Refer to Genetics

  20. Baby with multiple congenital abnormalities Alive Stillborn Macerated Fresh SB • Cardiac blood (heparin) • Skin snip (saline) Skin snip (saline) QF-PCR T13, 18, 21, X, Y Karyotype Refer to Genetics

  21. Baby with multiple congenital abnormalities Alive Stillborn MCA - unknown Suspect trisomy 13 or 18 Macerated Fresh SB • Cardiac blood (heparin) • Skin snip (saline) Skin snip (saline) Blood (heparin) Blood (EDTA) QF-PCR T13, 18, 21, X, Y Karyotype Karyotype QF-PCR Negative Positive Refer to Genetics

  22. Queries and Referrals Division Human Genetics 011 – 489 9223 / 4

  23. Acknowledgments • Prof Arnold Christianson • Dr Tony Lane • Ms Julie Lampret • Ms Brenda Kruger

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