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• W3092984652 abstract "Embryonic chromosomal abnormalities are the major cause of miscarriage. An accurate, rapid, and cheap method of chromosome analysis in miscarriage is warranted in clinical practice. Thus, a high-throughput ligation-dependent probe amplification (HLPA)-based method of detecting aneuploidies and copy number variations in miscarriage was developed. A total of 1060 cases of miscarriage were assessed. Each specimen was subjected to quantitative fluorescence (QF)-PCR/HLPA and chromosomal microarray analysis (CMA) in parallel. All 1060 samples were successfully analyzed using both methods; of these samples, 1.7% (18/1060) were identified as having significant maternal cell contamination. Among the remaining 1042 cases without significant maternal cell contamination, QF-PCR/HLPA reached a diagnostic yield of 59.6% (621/1042), which is comparable to the yield of 60.3% (628/1042) with CMA. Compared with CMA results, the sensitivity and specificity of QF-PCR/HLPA in the identification of total pathogenic chromosomal abnormalities were 98.9% and 100%, respectively. Furthermore, the overall prevalence of chromosomal abnormalities in cases of spontaneous abortion was not significantly different from that in cases of recurrent miscarriage (61.3% versus 58.5%). In summary, QF-PCR/HLPA rapidly and accurately identified chromosomal abnormalities at a comparable performance and lower cost as compared with CMA. Combining simplicity and accuracy with cost-effectiveness, QF-PCR/HLPA may serve as a promising approach to routine genetic testing in miscarriage in clinical practice. Embryonic chromosomal abnormalities are the major cause of miscarriage. An accurate, rapid, and cheap method of chromosome analysis in miscarriage is warranted in clinical practice. Thus, a high-throughput ligation-dependent probe amplification (HLPA)-based method of detecting aneuploidies and copy number variations in miscarriage was developed. A total of 1060 cases of miscarriage were assessed. Each specimen was subjected to quantitative fluorescence (QF)-PCR/HLPA and chromosomal microarray analysis (CMA) in parallel. All 1060 samples were successfully analyzed using both methods; of these samples, 1.7% (18/1060) were identified as having significant maternal cell contamination. Among the remaining 1042 cases without significant maternal cell contamination, QF-PCR/HLPA reached a diagnostic yield of 59.6% (621/1042), which is comparable to the yield of 60.3% (628/1042) with CMA. Compared with CMA results, the sensitivity and specificity of QF-PCR/HLPA in the identification of total pathogenic chromosomal abnormalities were 98.9% and 100%, respectively. Furthermore, the overall prevalence of chromosomal abnormalities in cases of spontaneous abortion was not significantly different from that in cases of recurrent miscarriage (61.3% versus 58.5%). In summary, QF-PCR/HLPA rapidly and accurately identified chromosomal abnormalities at a comparable performance and lower cost as compared with CMA. Combining simplicity and accuracy with cost-effectiveness, QF-PCR/HLPA may serve as a promising approach to routine genetic testing in miscarriage in clinical practice. Early pregnancy loss, also called miscarriage, is the most common complication in first-trimester pregnancy. Approximately 10% to 15% of all clinically recognized pregnancies end in miscarriage, and about 1% of couples experience recurrent miscarriage (RM).1Rai R. Regan L. Recurrent miscarriage.Lancet. 2006; 368: 601-611Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar At least 50% of miscarriages are caused by embryonic chromosomal abnormalities, the majority (86%) of which are numeric abnormalities.2Goddijn M. Leschot N.J. Genetic aspects of miscarriage.Baillieres Best Pract Res Clin Obstet Gynaecol. 2000; 14: 855-865Crossref PubMed Scopus (184) Google Scholar In addition, chromosomal structural abnormalities that commonly include the ends of chromosomes are involved in 6% of miscarriages.2Goddijn M. Leschot N.J. Genetic aspects of miscarriage.Baillieres Best Pract Res Clin Obstet Gynaecol. 2000; 14: 855-865Crossref PubMed Scopus (184) Google Scholar, 3Sahoo T. Dzidic N. Strecker M.N. Commander S. Travis M.K. Doherty C. Tyson R.W. Mendoza A.E. Stephenson M. Dise C.A. Benito C.W. Ziadie M.S. Hovanes K. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges.Genet Med. 2017; 19: 83-89Crossref PubMed Scopus (70) Google Scholar, 4Wang Y. Li Y. Chen Y. Zhou R. Sang Z. Meng L. Tan J. Qiao F. Bao Q. Luo D. Peng C. Wang Y.S. Luo C. Hu P. Xu Z. Systematic analysis of copy-number variations associated with early pregnancy loss.Ultrasound Obstet Gynecol. 2020; 55: 96-104Crossref PubMed Scopus (14) Google Scholar The use of genetic evaluation of products of conception (POCs) often provides a definite cause of miscarriage, which could decrease the psychological burden associated with miscarriage and reduce unnecessary testing and treatment.5Foyouzi N. Cedars M.I. Huddleston H.G. Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss.Fertil Steril. 2012; 98: 151-155Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,6Popescu F. Jaslow C.R. Kutteh W.H. Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients.Hum Reprod. 2018; 33: 579-587Crossref PubMed Scopus (47) Google Scholar Furthermore, the identification of specific chromosomal abnormalities may help to uncover parental balanced rearrangements, which would improve genetic counseling about recurrence risks in subsequent pregnancies and future reproductive choices.7Dahdouh E.M. Balayla J. Audibert F. Genetics C. Wilson R.D. Audibert F. Brock J.A. Campagnolo C. Carroll J. Chong K. Gagnon A. Johnson J.A. MacDonald W. Okun N. Pastuck M. Vallee-Pouliot K. Technical update: preimplantation genetic diagnosis and screening.J Obstet Gynaecol Can. 2015; 37: 451-463Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The ideal chromosome testing of POCs should be accurate, rapid, and inexpensive. However, current methods of chromosome analysis of POCs have limitations. G-band karyotyping, the gold standard of chromosome analysis, is laborious and requires live cells. Furthermore, this technique is hampered by high rates of culture failure, microbial contamination, and low resolution.8Shearer B.M. Thorland E.C. Carlson A.W. Jalal S.M. Ketterling R.P. Reflex fluorescent in situ hybridization testing for unsuccessful product of conception cultures: a retrospective analysis of 5555 samples attempted by conventional cytogenetics and fluorescent in situ hybridization.Genet Med. 2011; 13: 545-552Crossref PubMed Scopus (51) Google Scholar Targeted molecular assays, such as multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, quantitative fluorescence (QF)-PCR, and Bacterial Artificial Chromosomes–on-Beads (PerkinElmer, Waltham, MA), facilitate the rapid detection of chromosomal abnormalities at relatively low costs. However, the use of these methods is limited by restricted resolution and coverage of the whole genome.9Vermeesch J.R. Fiegler H. de Leeuw N. Szuhai K. Schoumans J. Ciccone R. Speleman F. Rauch A. Clayton-Smith J. Van Ravenswaaij C. Sanlaville D. Patsalis P.C. Firth H. Devriendt K. Zuffardi O. Guidelines for molecular karyotyping in constitutional genetic diagnosis.Eur J Hum Genet. 2007; 15: 1105-1114Crossref PubMed Scopus (129) Google Scholar Chromosomal microarray analysis (CMA) and next-generation sequencing facilitate the simultaneous detection of numeric and submicroscopic abnormalities at the whole-genome level.3Sahoo T. Dzidic N. Strecker M.N. Commander S. Travis M.K. Doherty C. Tyson R.W. Mendoza A.E. Stephenson M. Dise C.A. Benito C.W. Ziadie M.S. Hovanes K. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges.Genet Med. 2017; 19: 83-89Crossref PubMed Scopus (70) Google Scholar,4Wang Y. Li Y. Chen Y. Zhou R. Sang Z. Meng L. Tan J. Qiao F. Bao Q. Luo D. Peng C. Wang Y.S. Luo C. Hu P. Xu Z. Systematic analysis of copy-number variations associated with early pregnancy loss.Ultrasound Obstet Gynecol. 2020; 55: 96-104Crossref PubMed Scopus (14) Google Scholar,10Levy B. Sigurjonsson S. Pettersen B. Maisenbacher M.K. Hall M.P. Demko Z. Lathi R.B. Tao R. Aggarwal V. Rabinowitz M. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis.Obstet Gynecol. 2014; 124: 202-209Crossref PubMed Scopus (108) Google Scholar, 11Zhang Y.X. Zhang Y.P. Gu Y. Guan F.J. Li S.L. Xie J.S. Shen Y. Wu B.L. Ju W. Jenkins E.C. Brown W.T. Zhong N. Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and array CGH.Clin Genet. 2009; 75: 133-140Crossref PubMed Scopus (60) Google Scholar, 12Gao J. Liu C. Yao F. Hao N. Zhou J. Zhou Q. Zhang L. Liu X. Bian X. Liu J. Array-based comparative genomic hybridization is more informative than conventional karyotyping and fluorescence in situ hybridization in the analysis of first-trimester spontaneous abortion.Mol Cytogenet. 2012; 5: 33Crossref PubMed Scopus (35) Google Scholar, 13Lathi R.B. Massie J.A. Loring M. Demko Z.P. Johnson D. Sigurjonsson S. Gemelos G. Rabinowitz M. Informatics enhanced SNP microarray analysis of 30 miscarriage samples compared to routine cytogenetics.PLoS One. 2012; 7: e31282Crossref PubMed Scopus (31) Google Scholar, 14Viaggi C.D. Cavani S. Malacarne M. Floriddia F. Zerega G. Baldo C. Mogni M. Castagnetta M. Piombo G. Coviello D.A. Camandona F. Lijoi D. Insegno W. Traversa M. Pierluigi M. First-trimester euploid miscarriages analysed by array-CGH.J Appl Genet. 2013; 54: 353-359Crossref PubMed Scopus (32) Google Scholar, 15Bug S. Solfrank B. Schmitz F. Pricelius J. Stecher M. Craig A. Botcherby M. Nevinny-Stickel-Hinzpeter C. Diagnostic utility of novel combined arrays for genome-wide simultaneous detection of aneuploidy and uniparental isodisomy in losses of pregnancy.Mol Cytogenet. 2014; 7: 43Crossref PubMed Scopus (23) Google Scholar, 16Lin S.B. Xie Y.J. Chen Z. Zhou Y. Wu J.Z. Zhang Z.Q. Shi S.S. Chen B.J. Fang Q. Improved assay performance of single nucleotide polymorphism array over conventional karyotyping in analyzing products of conception.J Chin Med Assoc. 2015; 78: 408-413Crossref PubMed Scopus (17) Google Scholar, 17Rosenfeld J.A. Tucker M.E. Escobar L.F. Neill N.J. Torchia B.S. McDaniel L.D. Schultz R.A. Chong K. Chitayat D. Diagnostic utility of microarray testing in pregnancy loss.Ultrasound Obstet Gynecol. 2015; 46: 478-486Crossref PubMed Scopus (37) Google Scholar, 18Shen J. Wu W. Gao C. Ochin H. Qu D. Xie J. Gao L. Zhou Y. Cui Y. Liu J. Chromosomal copy number analysis on chorionic villus samples from early spontaneous miscarriages by high throughput genetic technology.Mol Cytogenet. 2016; 9: 7Crossref PubMed Scopus (31) Google Scholar, 19Warren J.E. Turok D.K. Maxwell T.M. Brothman A.R. Silver R.M. Array comparative genomic hybridization for genetic evaluation of fetal loss between 10 and 20 weeks of gestation.Obstet Gynecol. 2009; 114: 1093-1102Crossref PubMed Scopus (39) Google Scholar, 20Wang Y. Cheng Q. Meng L. Luo C. Hu H. Zhang J. Cheng J. Xu T. Jiang T. Liang D. Hu P. Xu Z. Clinical application of SNP array analysis in first-trimester pregnancy loss: a prospective study.Clin Genet. 2017; 91: 849-858Crossref PubMed Scopus (42) Google Scholar, 21Pauta M. Grande M. Rodriguez-Revenga L. Kolomietz E. Borrell A. Added value of chromosomal microarray analysis over karyotyping in early pregnancy loss: systematic review and meta-analysis.Ultrasound Obstet Gynecol. 2018; 51: 453-462Crossref PubMed Scopus (18) Google Scholar Nonetheless, the use of these technologies has some limitations, such as high costs and the challenges of interpretation and genetic counseling for variants of uncertain significance.22Westerfield L. Darilek S. van den Veyver I.B. Counseling Challenges with variants of uncertain significance and incidental findings in prenatal genetic screening and diagnosis.J Clin Med. 2014; 3: 1018-1032Crossref PubMed Scopus (50) Google Scholar High-throughput ligation-dependent probe amplification (HLPA), a new method modified from multiplex ligation-dependent probe amplification, has been demonstrated to be a rapid, accurate, and inexpensive technique for the detection of aneuploidy in miscarriage.23Yang L. Tang Y. Lu M. Yang Y. Xiao J. Wang Q. Yang C. Tao H. Xiang J. Novel rapid molecular diagnosis of fetal chromosomal abnormalities associated with recurrent pregnancy loss.Acta Obstet Gynecol Scand. 2016; 95: 1433-1440Crossref PubMed Scopus (4) Google Scholar,24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar However, in previous studies,23Yang L. Tang Y. Lu M. Yang Y. Xiao J. Wang Q. Yang C. Tao H. Xiang J. Novel rapid molecular diagnosis of fetal chromosomal abnormalities associated with recurrent pregnancy loss.Acta Obstet Gynecol Scand. 2016; 95: 1433-1440Crossref PubMed Scopus (4) Google Scholar,24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar microdeletions and microduplications (<10 Mb), as well as the majority of partial aneuploidies (≥10 Mb), in miscarriage could not be identified using HLPA. Therefore, a rapid and inexpensive method of simultaneous identification of aneuploidies, partial aneuploidies, and pathogenic microdeletions and/or duplications, based on an improved HLPA method, was developed, and its efficacy and diagnostic power were evaluated using QF-PCR/HLPA in parallel with CMA in >1000 consecutive cases of miscarriage. A prospective, double-blind study was conducted at the Prenatal Diagnostic Center, Nanjing Maternity and Child Health Care Hospital (Jiangsu, China), between April 2018 and January 2020. Women who had pregnancy loss before 13 weeks' gestation and requested genetic analysis of POCs were enrolled. Informed consent was obtained from all patients. RM was defined as two or more pregnancy losses. The mean maternal age was 30.7 years (range, 18 to 46 years), and the mean gestational age was 9.2 weeks (range, 6 to 13 weeks). Chorionic villi were collected from specimens of POCs using a standard method.25Lathi R.B. Milki A.A. Tissue sampling technique affects accuracy of karyotype from missed abortions.J Assist Reprod Genet. 2002; 19: 536-538Crossref PubMed Scopus (46) Google Scholar Specimens in which chorionic villi could not be clearly identified were excluded. The study protocol was approved by the Medicine Ethics Committee of Nanjing Maternity and Child Health Care Hospital. QF-PCR/HLPA and CMA were performed in parallel for the detection of chromosomal abnormalities. The testing strategies for the genetic analysis of POCs are summarized in Figure 1. DNA was isolated from specimens of POCs using the QIAamp DNA MiniKit (Qiagen, Hilden, Germany). Subsequently, each qualified DNA sample was divided into two equal parts for QF-PCR/HLPA and CMA. For the QF-PCR/HLPA strategy, all samples were investigated using the QF-PCR method for triploidy, whole-genome uniparental disomy (UPD), and maternal cell contamination (MCC). Cases without significant MCC were subsequently subjected to HLPA for the identification of aneuploidies and copy number variations (CNVs). Tetraploidy cannot be detected using QF-PCR/HLPA. For the CMA strategy, all samples were directly analyzed using single-nucleotide polymorphism (SNP) array, which can be used for the simultaneous identification of aneuploidies, polyploidies, CNVs, UPD, as well as MCC. Cases with significant MCC (>30%) were excluded from the study. The CytoScan 750K array (Affymetrix, Santa Clara, CA), comprising about 550,000 oligonucleotide probes and 200,000 SNP probes, was applied for the whole-genome scan. SNP array experiments were performed as previously reported,4Wang Y. Li Y. Chen Y. Zhou R. Sang Z. Meng L. Tan J. Qiao F. Bao Q. Luo D. Peng C. Wang Y.S. Luo C. Hu P. Xu Z. Systematic analysis of copy-number variations associated with early pregnancy loss.Ultrasound Obstet Gynecol. 2020; 55: 96-104Crossref PubMed Scopus (14) Google Scholar and molecular karyotype analysis was performed using ChAS software version 3.2 (Affymetrix). CNVs were called at an effective minimal resolution of 100 Kb, and regions of allelic homozygosity were reported at a threshold of 5 Mb. Mosaicism for aneuploidies or CNVs of ≥5 Mb was reported when it was above the detection threshold of 30%. MCC was reported when the levels of MCC exceeded the threshold of 30%. CNV classification was performed according to the American College of Medical Genetics guideline.26Kearney H.M. Thorland E.C. Brown K.K. Quintero-Rivera F. South S.T. Working Group of the American College of Medical Genetics Laboratory Quality Assurance CommitteeAmerican College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants.Genet Med. 2011; 13: 680-685Crossref PubMed Scopus (582) Google Scholar QF-PCR was performed using the Human Personal Identification Detection Kit (catalog number R1006; Genesky, Suzhou, China) as previously reported.24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar A total of 17 microsatellite markers were used for detecting MCC, triploidy, and whole-genome UPD, including 16 markers for autosomes (D2S1338, D5S818, D7S820, D8S1179, TH01, Vwa, D13S317, D16S539, D18S51, D8S588, G4S0001, G2S0002, G15S0001, G7S0005, G10S0001, and G5S0001) and 1 marker for sex chromosomes (Amelo). PCR products were analyzed using the ABI 3730XL automated sequencer (Applied Biosystems, Foster City, CA), and results were analyzed using ABI GeneMapper software version 5.0 (Applied Biosystems). On the basis of a previously published HLPA assay that contained 170 pairs of probes targeting all 24 chromosomes for the detection of aneuploidies23Yang L. Tang Y. Lu M. Yang Y. Xiao J. Wang Q. Yang C. Tao H. Xiang J. Novel rapid molecular diagnosis of fetal chromosomal abnormalities associated with recurrent pregnancy loss.Acta Obstet Gynecol Scand. 2016; 95: 1433-1440Crossref PubMed Scopus (4) Google Scholar,24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar (Supplemental Table S1), the method was improved by the addition of 171 pairs of probes that targeted chromosomal terminal regions to achieve a higher resolution for the identification of CNVs (Supplemental Table S2). As a result, a total of 341 pairs of probes for the detection of aneuploidies and CNVs were included in the current assay. The distribution of 341 probes that targeted all of the chromosomes is shown in Supplemental Figure S1. Among them, 3 probes at the end of each chromosome (with approximately 10 Mb genomic distance between each probe), and 2 probes at pericentromeric regions, were used as previously reported.24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar Meanwhile, probes were added to target the range of 0 to 5 Mb from the end of each chromosome, at a mean of approximately 1 probe per 1 Mb. The experiment was performed as previously described.24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar In brief, genomic DNA was denatured, hybridized, ligated, and amplified using the Human 24 Chromosome Copy Number Detection Kit (catalog number N1002S; Genesky). Similar to multiplex ligation-dependent probe amplification, each probe comprised an adapter sequence for binding with universal primers and a target-specific sequence complementary to the target regions. Compared with multiplex ligation-dependent probe amplification, HLPA introduced a lengthening ligation system as well as four types of 5′ universal primers labeled with different fluorophores combined with two types of 3′ primers to achieve a higher throughput.24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar PCR products were analyzed using an ABI 3730XL automated sequencer, and data were analyzed using GeneMapper software version 5.0 (both from Applied Biosystems). Copy number was calculated as previously reported.24Chen S. Liu D. Zhang J. Li S. Zhang L. Fan J. Luo Y. Qian Y. Huang H. Liu C. Zhu H. Jiang Z. Xu C. A copy number variation genotyping method for aneuploidy detection in spontaneous abortion specimens.Prenat Diagn. 2017; 37: 176-183Crossref PubMed Scopus (8) Google Scholar In this study, CNV values between 1.7 and 2.3 were considered normal. CNV values from at least three consecutive probes targeting one chromosome below 1.5 and above 2.5 were representative of deletions and duplications, respectively. For duplications, values between 2.5 and <3.5 and between 3.5 and <4.5 were determined as three copies and four copies, respectively. In addition, values between 1.5 and 1.7 suggested mosaic deletions, while those between 2.3 and 2.5 indicated mosaic duplications. Comparisons between groups were performed using the χ2 test or Fisher exact test. A P value of <0.05 was considered as statistically significant. A total of 1060 tissues obtained from miscarriages were analyzed using QF-PCR/HLPA and CMA in parallel. Significant MCC was identified in 18 cases (1.7%) by both methods (Figure 1). Among the remaining 1042 cases with no or negligible MCC, pathogenic chromosomal abnormalities were identified in 628 cases with CMA, providing a diagnostic yield of 60.3% (Table 1). In comparison, chromosomal abnormalities were detected in 621 (59.6%) cases with QF-PCR/HLPA. Seven cases (0.7%) with CNVs were missed using QF-PCR/HLPA, including 3 (0.3%) with partial aneuploidies and 4 (0.4%) with pathogenic microdeletions and/or duplications. Compared with CMA results, the sensitivity and specificity of QF-PCR/HLPA in the identification of total pathogenic chromosomal abnormalities were 98.9% and 100.0%, respectively (Table 2). The cost of QF-PCR/HLPA was remarkably lower than that of CMA ($114.30 versus $514.30 per case). The turnaround time with QF-PCR/HLPA was 1 day, which was shorter than that with CMA (3 to 4 days).Table 1Diagnostic Yields in 1042 Miscarriage Cases with CMA and QF-PCR/HLPAChromosomal abnormalityCMAQF-PCR/HLPATotalSARMP valueTotalSARMSingle aneuploidy488 (46.8)312 (47.9)176 (45.1)0.394488 (46.8)312 (47.9)176 (45.1) Autosomal trisomy391 (37.5)248 (38)143 (36.7)0.658391 (37.5)248 (38)143 (36.7) Autosomal monosomy2 (0.2)2 (0.3)00.5312 (0.2)2 (0.3)0 Monosomy X93 (8.9)61 (9.4)32 (8.2)0.52893 (8.9)61 (9.4)32 (8.2) Trisomy (sex chromosome)2 (0.2)1 (0.2)1 (0.3)1.0002 (0.2)1 (0.2)1 (0.3)Multiple aneuploidy18 (1.7)12 (1.8)6 (1.5)0.71718 (1.7)12 (1.8)6 (1.5) Double aneuploidy18 (1.7)12 (1.8)6 (1.5)0.71718 (1.7)12 (1.8)6 (1.5)Polyploidy80 (7.7)55 (8.4)25 (6.4)0.23580 (7.7)55 (8.4)25 (6.4) Triploidy66 (6.3)49 (7.5)17 (4.4)0.04366 (6.3)49 (7.5)17 (4.4) Hypertriploidy9 (0.9)3 (0.5)6 (1.5)0.1409 (0.9)3 (0.5)6 (1.5) Hypotriploidy5 (0.5)3 (0.5)2 (0.5)1.0005 (0.5)3 (0.5)2 (0.5)Partial aneuploidy30 (2.9)17 (2.6)13 (3.3)0.49827 (2.6)16 (2.5)11 (2.8) Terminal deletion or duplication11 (1.1)7 (1.1)4 (1.0)1.00011 (1.1)7 (1.1)4 (1.0) Terminal deletion + terminal duplication (suggestive of unbalanced translocation)8 (0.8)3 (0.5)5 (1.3)0.2698 (0.8)3 (0.5)5 (1.3) Interstitial deletion or duplication3 (0.3)1 (0.2)2 (0.5)0.652000 Multiple deletions and/or duplications8 (0.8)6 (0.9)2 (0.5)0.7178∗Two cases were identified as terminal deletion or duplication using HLPA, and one case was detected as terminal deletion coupled with terminal duplication. (0.8)6 (0.9)2 (0.5)Pathogenic microdeletion or duplication7 (0.7)2 (0.3)5 (1.3)0.1413 (0.3)2 (0.3)1 (0.3) Terminal microdeletion or duplication3 (0.3)2 (0.3)1 (0.3)1.0003 (0.3)2 (0.3)1 (0.3) Interstitial microdeletion or duplication4 (0.4)04 (1.0)0.038000UPD5 (0.5)2 (0.3)3 (0.8)0.5605 (0.5)2 (0.3)3 (0.8) Whole-genome UPD5 (0.5)2 (0.3)3 (0.8)0.5605 (0.5)2 (0.3)3 (0.8)Total628 (60.3)400 (61.3)228 (58.5)0.357621 (59.6)399 (61.2)222 (56.9)Data are expressed as n (%).CMA, chromosomal microarray analysis; QF-PCR/HLPA, quantitative fluorescence PCR/high-throughput ligation-dependent probe amplification; RM, recurrent miscarriage; SA, spontaneous abortion; UPD, uniparental disomy.∗ Two cases were identified as terminal deletion or duplication using HLPA, and one case was detected as terminal deletion coupled with terminal duplication. Open table in a new tab Table 2Efficiency of QF-PCR/HLPA in Cases of MiscarriageChromosomal abnormalityCMA as reference, nQF-PCR/HLPA, nSensitivity, %Specificity, %Numeric chromosomal abnormalities586586100100Partial aneuploidy302790.0100Pathogenic microdeletion or duplication7342.9100Whole-genome UPD55100100Total62862198.9100CMA, chromosomal microarray analysis; QF-PCR/HLPA, quantitative fluorescence PCR/high-throughput ligation-dependent probe amplification; UPD, uniparental disomy. Open table in a new tab Data are expressed as n (%). CMA, chromosomal microarray analysis; QF-PCR/HLPA, quantitative fluorescence PCR/high-throughput ligation-dependent probe amplification; RM, recurrent miscarriage; SA, spontaneous abortion; UPD, uniparental disomy. CMA, chromosomal microarray analysis; QF-PCR/HLPA, quantitative fluorescence PCR/high-throughput ligation-dependent probe amplification; UPD, uniparental disomy. The QF-PCR/HLPA approach was 100% consistent with CMA analysis in identifying numeric chromosomal abnormalities and whole-genome UPD (Table 1). Numeric chromosomal abnormalities were observed in 586 cases (56.2%), including 506 (48.6%) with aneuploidies and 80 (7.7%) with triploidies. Among the cases with aneuploidies, single aneuploidies represented 96.4% (488/506) of these cases, and multiple aneuploidies composed the remaining 3.6% (18/506). Aneuploidy was identified in all chromosomes except 1 and 19. The majority of single aneuploidies were chromosomal trisomies (393/488, 80.5%), and the others were monosomies (95/488, 19.5%). Among the cases with single trisomies, trisomy 16 was the most common (128/393, 32.6%), followed by trisomy 22 (67/393, 17.0%) and trisomy 13 (31/393, 7.9%) (Supplemental Figure S2). With respect to monosomies, monosomy X accounted for 97.9% (93/95) of these cases, whereas autosomal monosomy represented the remaining 2.1% (2/95) (2 cases with monosomy 21). Of the 6 cases with mosaic aneuploidies identified using CMA, 3 (2 cases with mosaic trisomy 16, and 1 case with mosaic trisomy 5) were also identified as mosaic aneuploidies using HLPA, whereas the other 3 (1 case with mosaic trisomy 22, 1 case with mosaic trisomy 7, and 1 case with mosaic monosomy X) were found to be nonmosaic aneuploidies owing to a relatively high proportion of aneuploidies. In addition, whole-genome UPD, which was suggestive of a molar pregnancy, was detected using both methods in 5 cases (0.5%). Partial aneuploidies (CNVs ≥10 Mb) were identified using CMA in 30 miscarriage cases (2.9%) (Table 1 and Supplemental Table S3). These included 11 cases (1.1%) with terminal deletion or duplication, 8 (0.8%) with terminal deletion coupled with terminal duplication (unbalanced translocation), 3 (0.3%) with interstitial deletion or duplication, and 8 (0.8%) with multiple deletions and/or duplications (two or more CNVs involving single or multiple chromosomes). In comparison, 27 of these 30 cases were detected using HLPA, providing a sensitivity of 90.0%. Because no false-positive results were detected using HLPA, the specificity of identifying partial aneuploidies was 100%. Among the 27 cases with partial aneuploidies detected using HLPA, completely concordant results were observed in 24 cases, whereas incompletely concordant results (consistent CNVs were identified using both methods but more pathogenic CNVs were detected using CMA than HLPA) were identified in 3 cases (Supplemental Figure S3). Among these 3 cases with incompletely concordant results diagnosed as multiple deletions and/or duplications using CMA, 2 were identified as terminal deletion or duplication using HLPA, and 1 was detected as terminal deletion coupled with terminal duplication. The reason for the incompletely concordant results was that interstitial deletion or duplication contained in cases with multiple deletions and/or duplications could not be detected u" @default.
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• W3092984652 date "2021-01-01" @default.
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• W3092984652 title "Identification of Chromosomal Abnormalities in Early Pregnancy Loss Using a High-Throughput Ligation-Dependent Probe Amplification–Based Assay" @default.
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