ida vogel nnfm 150415
TRANSCRIPT
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Danish experiences with Chromosomal Micro-Array (CMA) in a prenatal setting
Ida Vogel MD, PhD, Clinical Genetics, Aarhus University Hospital Denmark [email protected]
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Since 2004-
All Danish women are offered: • combined First Trimester Screening (93%)
• Double test (PAPP-A/fβhCG) • NT scan • Age
• Anomaly scan (96%)
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Post- and prenatal Downs syndrom diagnoses
0
20
40
60
80
100
120
140
2000 2002 2004 2006 2008 2010
Postnatal Prænatal Data from DCCR
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Abortions in Denmark • Large increase (>100%) in late abortions after new
screening criteria in 2004
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Mette Svane Bech, Jette Sørensen and Olav Bjørn Petersen
90
166
4 0 25
265
7 0 0
50
100
150
200
250
300
Lethal Severe Moderate minor
No.
of c
ases
Severity
Severity of structural anomalies after TOP. N=557, 2007-2014
<17 weeks of gestation ≥17 weeks of gestation
Saltved et al. BJOG, 2006 Jun;113(6):664-74
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Neonatal death due to chromosomal/fetal anomalies
0
50
100
150
200
250
2000 2002 2004 2006 2008 2010
No/year
SST: Dødsårsagsregistret 2000-2011
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Prenatal screening tools
Assay Chromosome diseases
Screen og diagnostic test
Risk of miscarriage
NIPT T21, T18, T13 +sex Screen - QFPCR/MLPA T21, T18, T13 +sex Diagnostic 0.22%* cFTS >>10 Screen - Chromosome analyses
10-100 Diagnostic 0.22%*
Chromosomal Micro Array
>1000 Diagnostic 0.22%*
*Akolekar et al, UOG 2015; 45:16-26
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Chromosomal microarray CMA
Patient DNA
Control DNA
Rat
io
Position on Sequence
Hybridize
Quantitate
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Detection Rate (DR): CMA: 10% (CI 8-12%) Chromosomal analyses 3%
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Consensus 2010
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CMA in pregnancy – 2010
Additional Detection Rate by CMA • All indications +3,6% • Structural malformation +5,2%
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2013 Meta-analyses N=12,362 DR CMA after normal karyotype
– All indications +2.4 % – Abnormal UL +6.5 %
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January 2013
National guideline (DSOG, DSMG) • CMA is first tier analysis in pregnancy for:
– Malformations – NT >= 3,5mm – Small biometries in 2nd-3rd trimester – Intra-Uterine Death
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Aarhus, 1036 prenatal cases
1. Aneuploidy (13, 18, 21, X, Y) 2.0 %
2. Pathogenic variation (CNV) 7.9 %
3. Variation of Unknown Significance (VUS) 1.2 %
Clinical significant finding (1+2+3) 11.1 %
More than karyotype (2+3) 9.1 %
4. Familiar variation (CNV) 3.2 %
5. Incidental finding (STS, DMD) 0.7 % Turn Around Time <7 working days
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Acta Obstet Gynecol Scand. 2013 Jul;92(7):762-8
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Case Indication (14+1): malformed upper extremities, micrognathia, small head
0.4 Mb deletion, chromosome 1, de novo SF3B4: Nager acrofacial dysostosis (OMIM #154400) Malformation of the craniofacial skeleton and the limbs
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Nager syndrome (acrofacial dysostosis)
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Case
• Facial cleft w 19 • No other malformations. • Tertiary scan by fetal
medicin expert • aCGH result after 4 days is normal
• MAJORITY of cases (85%)
”In the absence of associated anomalies, chromosomal defects were found prenatally in CLP (3.9%)” Maarse W et al. J Med Genet. 2012.
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NIH Study. 1,082 fetuses with malformations, 2032 without. (CNV=Pathogenic and VUS) • Heart: DR 16% • Face: DR 15% • Kidney DR 12% • One talipes DR 7%
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• Leung (Danish cohort) DR +8.3% • Donelly (US cohort) DR +5% • Huang ( Kings college Cohort) DR +1.4% • Lund (Danish cohort): DR +12.8%
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Low risk
• Fiorentino: DR +0.6% • Oneda: DR +1.6% • Warpner: DR +1.7% • Shaffer: DR +0.3% • DR of CMA is a little better than chromosome analyses
also in low risk pregnancies
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Carey: finds mosaicism > 9% Fiorentini: finds mosaicism >10% Hall: finds mosaicism >10-13% = chromosome analyses of 10 metaphases Risk of CPM? • 1.8% CVS • 0.46 % AM
Do we wish to know? False positive?
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32 years, GA 19 +2, 2 healthy children UL: IUGR
Trisomi 2 mosaicisme TAT: 4 days
Case
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”Gold standard” chromosomal analyses
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Case NT 7.5mm Risk T21 1:39
Uncultured CVS:
Cultured CVS:
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Wobbly legs when conselling in difficult CMA cases (VUS)?
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• Based on surveys completed by 193 prenatal genetic counselors, we found that when there is an uncertain CMA result, only 59% would be comfortable providing genetic counseling and only 43% would be comfortable helping a patient make a decision about pregnancy termination.
• Being less comfortable was associated with seeing fewer patients having prenatal CMA testing.
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Blog By Dr Cohen after Warpner et al. N Engl J Med 2012; 367;23:2175-2183
”One can only imagine the anxiety we would cause in our patients undergoing relatively routine testing when we informed them that their baby has a chromosomal abnormality, but it may or may not be normal. I can just hear myself telling a healthy 37 year old woman, “Your guess is as good as mine!”
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Stina Lou, PhD 2014, AU, Denmark Title: Exploring how clinicians, pregnant women, and their partners manage and negotiate a high risk screening result for chromosomal abnormality in the fetus
Conclusions: • Informed choice is insufficient • Care is necessary • Worry can be managed • Anxiety decrease
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Stina continued
• Sharing uncertainty democratizes the relationship between patient and doctor
Is this the key to how we manage variants of uncertain significance?
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Case GA 12+6 NT 3.8 mm
1.3 Mb duplication 1q21. Paternally inheritet Variant of unknown significance Penetrance incomplete (17%?). Increased risk of low IQ, autism, ADHD, dysmorphia. After counselling they decided to continue the pregnancy – as they knew about the problems of this family before-hand
!
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Multi Disciplinary set-up AUH • Weekly conferences fetal medicine experts + clinical
geneticists • Joint patient counselling • Fetal patologist • Pediatricians • Antropologists, • Counsellors, religious heads • Stepwise approach into changes • Our next step: CMA for risk >1:300 from 01.09.15
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AUH Conclusions on CMA • CMA finds aneuploidy, microdeletions and
microduplications. • Detection rate for CMA>>>> chromosome analysis >> NIPT • CMA is THE analysis of choice for high risk individuals • Few incidental findings • Meaningful and manageable • Much shorter turn around time (<7 days, median 4 days) • Experience helps! Centralize to large tertiary centers
• MUCH more important to implement CMA than NIPT - NOW
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Dr Cohens blog revisited It is easy to see that this is the beginning of a revolution in Medicine. It is likely that within a few years, we will combine NIPT with gene-sequencing to cause an explosion in the world of prenatal diagnosis. Here will lie the potential to prevent more disease than vaccination and even the possibility of extending the average human life span. These are exciting times and maternal-fetal medicine specialists would do well to hear the drums and to start expanding their training in and knowledge of human genetics in anticipation of this great medical revolution. Comment on Warpner. N Engl J Med 2012; 367;23:2175-2183
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Thanks! • Else Marie Vestergaard, Rikke
Christensen, Dept Clinical genetics, AUH
• Olav Bjørn Petersen, Departments of OBGYN, AUH+ Fetal medicine experts in region
• Mette Svane Bech, Medical student
• Helle Hørby, priest • Mette Ramsing, pathology
• Stina Lou Fleron, and Morten Deleuran Therkildsen, antropologists,
• Center of rare Diseases, AUH • Jon Hyett, Sydney • Cardiologists • Pediatricians • And more…