I Vogel1,2,3, O B Petersen2,4, R Christensen1,3, J Hyett5, S Lou2,6, E M Vestergaard1,2,3. 1. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 2. Center for Prenatal Diagnostics, Aarhus University Hospital, Aarhus, Denmark. 3. Institute of Biomedicine, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark. 5. Discipline of Obstetrics, Gynaecology and Neonatology, University of Sydney, Sydney, Australia. 6. DEFACTUM, Central Denmark Region, Denmark.
Abstract
OBJECTIVE: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS). METHODS: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings. RESULTS: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed. CONCLUSIONS: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening.
OBJECTIVE: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS). METHODS: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings. RESULTS: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed. CONCLUSIONS: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening.
Authors: Olav B Petersen; Eric Smith; Diane Van Opstal; Marike Polak; Maarten F C M Knapen; Karin E M Diderich; Caterina M Bilardo; Lidia R Arends; Ida Vogel; Malgorzata I Srebniak Journal: Acta Obstet Gynecol Scand Date: 2020-05-12 Impact factor: 3.636
Authors: Annisa Mak; Helena Lee; C F Poon; S L Kwok; Teresa Ma; K Y K Chan; Anita Kan; Mary Tang; K Y Leung Journal: BMC Pregnancy Childbirth Date: 2019-02-04 Impact factor: 3.007
Authors: Konstantin Ridnõi; Kai Muru; Maria Keernik; Sander Pajusalu; Eva-Liina Ustav; Pille Tammur; Triin Mölter-Väär; Tiina Kahre; Ustina Šamarina; Karin Asser; Ferenc Szirko; Tiia Reimand; Katrin Õunap Journal: Mol Genet Genomic Med Date: 2021-09-06 Impact factor: 2.183
Authors: Malgorzata I Srebniak; Maarten F C M Knapen; Lutgarde C P Govaerts; Marike Polak; Marieke Joosten; Karin E M Diderich; Laura J C M van Zutven; Krista A K E Prinsen; Sam Riedijk; Attie T J I Go; Robert-Jan H Galjaard; Lies H Hoefsloot; Diane Van Opstal Journal: Mol Genet Genomic Med Date: 2019-12-01 Impact factor: 2.183