20150918 F. Vialard - Prevalence of recurrent pathogenic microdeletion and microduplication in over 9.500 pregnancies by PrenatalBoBsTM
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This document discusses changes in prenatal screening and diagnosis. It describes a BACs-on-Beads technology called Prenatal BoBs that can detect pathogenic microdeletions and microduplications in pregnancies. A worldwide study of over 9,500 pregnancies found 44 cryptic imbalances not detectable by conventional methods, with an additive detection rate of 1/220. The majority (71.2%) involved the 22q11.2 region. The document discusses the potential role and limitations of Prenatal BoBs compared to chromosomal microarray analysis, and whether screening for 22q11.2 abnormalities should be done using non-invasive prenatal testing.
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20150918 F. Vialard - Prevalence of recurrent pathogenic microdeletion and microduplication in over 9.500 pregnancies by PrenatalBoBsTM
- 1. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prevalence of recurrent pathogenic microdeletion and microduplication in over 9.500 pregnancies by PrenatalBoBsTM François Vialard
- 2. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? The BACs-on-Beads technology
- 3. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Microsphere-based suspensionMicrosphere-based suspension array technologyarray technology The quantification of theThe quantification of the interaction that has occurred atinteraction that has occurred at the microsphere surface betweenthe microsphere surface between the BAC and the DNA targetthe BAC and the DNA target sequence is performed bysequence is performed by LuminexLuminex xMAP® systemxMAP® system Microspheres/beads conjugatedMicrospheres/beads conjugated with BAC probeswith BAC probes BACs-on-Beads Technology
- 4. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs Syndrome Trisomy 13 Trisomy 18 Trisomy 21 DiGeorge Williams-Beuren Prader-Willi Angelman Smith-Magenis Wolf-Hirschhorn Cri du Chat Langer-Giedion Miller-Dieker Incidence 1/10 000 1/6 000 1/800 1/4 000 1/7 500 1/20 000 1/15 000 1/20 000 1/50 000 1/30 000 Inconnue 1/100 000 Detection rate 100 % 95% 100% 95% 95% 75% 68% 95% 95% 99% 95% 90%
- 5. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? 3/3 BACs unbalanced 46 100% 1/3 or 2/3 BACs unbalanced 12 0/12 (0%) All 3/3 BACs unbalanced 154 152 (98,7%) Terminal unbalanced(p et q) 58 38(65,5%) Karyolite BoBs
- 6. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs
- 7. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BACs-on-BeadsTM A world collaborative study TOMA, Busto Arsizio (VA), ItalyTOMA, Busto Arsizio (VA), Italy Francesca GratiFrancesca Grati Livia MarcatoLivia Marcato CHI Poissy St Germain,CHI Poissy St Germain, François VialardFrançois Vialard Denise Molina GomesDenise Molina Gomes Hôpital Robert Debré,Hôpital Robert Debré, Brigitte BenzackenBrigitte Benzacken Anne Claude TabetAnne Claude Tabet Céline DupontCéline Dupont Iviomics SL, Valence,Iviomics SL, Valence, Jose Antonio Martínez-ConejeroJose Antonio Martínez-Conejero Sandra Garcia-HerreroSandra Garcia-Herrero Pomeranian Medical University,Pomeranian Medical University, Szczecin,Szczecin, Krzysztof PiotrowskiKrzysztof Piotrowski Stanislaw ZajaczekStanislaw Zajaczek University ''Federico II'',University ''Federico II'', Naples, ItalyNaples, Italy Rita GenesioRita Genesio Lucio NitschLucio Nitsch Ospedale San PietroOspedale San Pietro Fatebenefratelli,Fatebenefratelli, RomeRome, Italy, Italy Viola AlesiViola Alesi United MedixUnited Medix Laboratories Ltd., Helsinki,Laboratories Ltd., Helsinki, Nina Horelli-KuitunenNina Horelli-Kuitunen Hopital General de México,Hopital General de México, Faculté de Médecine,Faculté de Médecine, MexiqueMexique Gloria QueipoGloria Queipo Prince of Wales Hospital,Prince of Wales Hospital, Chinese UniversityChinese University of Hong Kong, Shatinof Hong Kong, Shatin Kwong Wai ChoyKwong Wai Choy CGC GeneticsCGC Genetics Alberto GonzalesAlberto Gonzales MadridMadrid CHU Clermond Ferrand,CHU Clermond Ferrand, Philippe VagoPhilippe Vago Laetitia GouasLaetitia Gouas
- 8. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs worldwide study 64%: low risk pregnancy 25%: high risk pregnancy 11%: Unknwon or undetailed ultrasound indication
- 9. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs worldwide study
- 10. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Additive detection rate for kit Prenatal BoB 44 microdeletions or duplications no identifiable by conventionnal cytogenetic technics Additive detection rate is then at : 1/220 (44/9648) Considering only low risk pregnancies 1/300 (20/5953) Considering only high risk pregnancies 1/110 (21/2311)
- 11. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs worldwide study CRITICAL REGIONCRITICAL REGION LOSSLOSS GAINGAIN 22q11.222q11.2 (DGS)(DGS) ~1/300 (32)~1/300 (32) ~1/600 (15)~1/600 (15) 15q11.215q11.2 (PWS/AS)(PWS/AS) <1/10000 (NF)<1/10000 (NF) ~1/1600 (6)~1/1600 (6) 7q11.237q11.23 (WBS)(WBS) ~1/2300 (4)~1/2300 (4) ~1/9300 (1)~1/9300 (1) 4p16.34p16.3 (WHS)(WHS) ~1/2300 (4)~1/2300 (4) <1/10000 (NF)<1/10000 (NF) 17p1317p13 (MDS)(MDS) ~1/4700 (2)~1/4700 (2) ~1/9300 (1)~1/9300 (1) 17p1117p11 (SMS)(SMS) <1/10000 (NF)<1/10000 (NF) ~1/9300 (1)~1/9300 (1)
- 12. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Prenatal BoBs worldwide study Majority (47/66; 71.2%) involved the 22q11.2 (DGS-CR):Majority (47/66; 71.2%) involved the 22q11.2 (DGS-CR): • del22q11.2 (all indications): 1/291* (n=32)del22q11.2 (all indications): 1/291* (n=32) • dup22q11.2 (all indications): 1/622* (n=15)dup22q11.2 (all indications): 1/622* (n=15) The remaining cryptic imbalances showed an incidence <1:1000.The remaining cryptic imbalances showed an incidence <1:1000.
- 13. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Critical regions never identified in gain or loss 5p155p15 Cri-du-ChatCri-du-Chat 8q238q23 Langer-GiedionLanger-Giedion 10p1410p14 DiGeorge-2DiGeorge-2 17p1317p13 Miller Diecker (G/L only in HR population)Miller Diecker (G/L only in HR population) 15q11.215q11.2 PWS/AS (PWS/AS (NO Losses in the entire cohortNO Losses in the entire cohort)) Prenatal BoBs worldwide study
- 14. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? p<0.05 p<0.05 Prenatal BoBs worldwide study Cryptic CNVs are not maternal age dependent and in particular del22q11.2 (Besseau et al, 2014)
- 15. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? But, what is its place in comparison to CMA ? CMA is recommended for all pregnancy with ultrasound findings Is there a place if CMA will be recommended for all invasive procedure
- 16. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Limites of BACs-on-Beads technology Regions analysed by the Prénatal BoBs kit Detection rate according to Cooper et al Wolf Hirchhorn 1.9% 5p- 0.0% Williams 3.9% Langer Giedon 0.9% 10p14 0.0% PWS/AS 2.9% MDS 2.3% SMS 1.7% DGS 9.8% Total 23.4%
- 17. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Regions analysed by the Prénatal BoBs kit Detection rate according to Cooper et al 1p36 6.4% 3q29 0.6% Wolf Hirchhorn 1.9% Cri du Chat 0.0% Sotos 0.6% Williams 3.9% Kleefstra 4.3% PWS/AS 2.9% Jacobsen 0.0% Rétinoblastome 0.0% MDS 2.3% SMS 1.7% 17q21.31 1.7% DGS 9.8% Total 36.1% 1q21.1 (7.4%), 2q37 (1.5%), 15q13.3 (4.2%), TBX6 (6.2%) et SHANK3 (3.5%) Total: 22.8% Kit upgrade
- 18. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Which syndromes to screen
- 19. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Technology upgrade 100 beads 500 beads 75 to 100 regions analysed
- 20. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? What could be the advantage of Prenatal BoB compared with CMA Easier Workflow Diagnosis rapidity Easier interpretation Cost
- 21. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Until CMA will be done and in place of rapid FISH analysis Is the Prenatal BoB had a place for low risk pregnancies ? CRITICAL REGIONCRITICAL REGION LOSSLOSS GAINGAIN 22q11.222q11.2 (DGS)(DGS) ~1/1000 (6)~1/1000 (6) ~1/1000 (7)~1/1000 (7) 15q11.215q11.2 (PWS/AS)(PWS/AS) <1/10000 (NF)<1/10000 (NF) ~1/2000 (3)~1/2000 (3) 7q11.237q11.23 (WBS)(WBS) ~1/3000 (2)~1/3000 (2) ~1/9300 (1)~1/9300 (1) 4p16.34p16.3 (WHS)(WHS) ~1/6000 (1)~1/6000 (1) <1/10000 (NF)<1/10000 (NF) 17p1317p13 (MDS)(MDS) <1/10000 (NF)<1/10000 (NF) <1/10000 (NF)<1/10000 (NF) 17p1117p11 (SMS)(SMS) <1/10000 (NF)<1/10000 (NF) ~1/6000 (1)~1/6000 (1)
- 22. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Do we need to screen for 22q11.2 abnormalities using NIPT ?
- 23. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? What is the 22q11.2 abnormalities phenotype penetrance
- 24. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? What is the 22q11.2 abnormalities inheritance Inheritance from healthy parent in 65% Inheritance from healthy parent in 13%
- 25. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Do we need to screen for 22q11.2 abnormalities using NIPT ? Could the low risk population be considered as general population ? What is the real 22q11.2 abnormalities penetrance ?
- 26. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Fetuses (Ultrasoundfindings) Fetuses (Foetopathologicalexamination) Newborns <1month Infants 1month–2years Children 3years–6years Children 7years–12years Adolescents 13years–19years Adults >19yearsEvolution of call signs for 22q11DS research according to age Violle Poirsier at al, in press
- 27. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? Do we need to screen for 22q11.2 abnormalities using NIPT ? What is the false positive rate ? Should the microrearrangment screening be at the origine of an increase number of invasive procedure ?
- 28. 18 Settembre 2015 ; TOMA Lab: La diagnosi prenatale e gli screening prenatali: Cosa sta cambiando? TOMA, Busto Arsizio (VA), ItalyTOMA, Busto Arsizio (VA), Italy Francesca GratiFrancesca Grati Livia MarcatoLivia Marcato CHI Poissy St Germain,CHI Poissy St Germain, François VialardFrançois Vialard Denise Molina GomesDenise Molina Gomes Hôpital Robert Debré,Hôpital Robert Debré, Brigitte BenzackenBrigitte Benzacken Anne Claude TabetAnne Claude Tabet Céline DupontCéline Dupont Iviomics SL, Valence,Iviomics SL, Valence, Jose Antonio Martínez-ConejeroJose Antonio Martínez-Conejero Sandra Garcia-HerreroSandra Garcia-Herrero Pomeranian Medical University,Pomeranian Medical University, Szczecin,Szczecin, Krzysztof PiotrowskiKrzysztof Piotrowski Stanislaw ZajaczekStanislaw Zajaczek University ''Federico II'',University ''Federico II'', Naples, ItalyNaples, Italy Rita GenesioRita Genesio Lucio NitschLucio Nitsch Ospedale San PietroOspedale San Pietro Fatebenefratelli,Fatebenefratelli, RomeRome, Italy, Italy Viola AlesiViola Alesi United MedixUnited Medix Laboratories Ltd., Helsinki,Laboratories Ltd., Helsinki, Nina Horelli-KuitunenNina Horelli-Kuitunen Hopital General de México,Hopital General de México, Faculté de Médecine,Faculté de Médecine, MexiqueMexique Gloria QueipoGloria Queipo Prince of Wales Hospital,Prince of Wales Hospital, Chinese UniversityChinese University of Hong Kong, Shatinof Hong Kong, Shatin Kwong Wai ChoyKwong Wai Choy CGC GeneticsCGC Genetics Alberto GonzalesAlberto Gonzales MadridMadrid CHU Clermond Ferrand,CHU Clermond Ferrand, Philippe VagoPhilippe Vago Laetitia GouasLaetitia Gouas Medical University of WarsawMedical University of Warsaw Jose FerreiraJose Ferreira
Notes de l'éditeur
- The estimated additional diagnostic yield of the Prenatal BoBsTM assay (in combination with conventional cytogenetic analysis) was ~1 in 240 including all 13 microdeletions and microduplications detectable only by PN_BoBsTM. When considering only low-risk pregnancies, this value is ~1 in 310. In these cases, a prenatal “genotype-first” approach enabled the detection of dominant and fully penetrant submicroscopic copy number aberrations long before discriminatory prenatal signs were visible on detailed ultrasound. Prenatal BoBsTM was able to detect 8 abnormal cases that would have been missed by a stand-alone QF-PCR approach and thus provided an additional diagnostic yield of ~1 in 270