Universal Prenatal Chromosomal Microarray Analysis: Additive Value and Clinical Dilemmas in Fetuses with a Normal Karyotype

Abstract

Objective To assess the additive value of prenatal chromosomal microarray analysis (CMA) for all indications and the likelihood of detecting pathologic copy number variations (CNVs) based on specific indications.

Methods A retrospective analysis was performed on amniocentesis and chorionic villi sampling results obtained between 2010 and 2014 in a single institution. A total of 3,314 consecutive patients undergoing invasive genetic testing for different indications were offered CMA in addition to standard karyotype. The prevalence of pathologic CNVs was compared between patients with low-risk indications and those with high-risk indications. Likewise, the prevalence of pathologic CNVs among patients with different sonographic abnormalities was calculated and compared with the low-risk group. Chi-square and Fisher exact tests were used for statistical analysis.

Results The prevalence of pathologic CNVs was significantly higher in patients with high-risk indications and specifically those with sonographic abnormalities, compared with the low-risk group (2.8 and 5.9% vs. 0.4%, respectively; all p < 0.05).

Conclusion Prenatal CMA detected clinically relevant CNVs in fetuses with a normal karyotype. Major structural malformations and nuchal translucency (NT) ≥ 3.0 mm are associated with the highest risk for a CMA abnormality. Nevertheless, the prevalence of pathologic CNVs in the low-risk population was high enough (1:250) to consider genetic counseling in this group.

Keywords

chromosomal microarray - genetic counseling - karyotype - prenatal diagnostic test

• References

• 1 Schmid M, Stary S, Blaicher W, Gollinger M, Husslein P, Streubel B. Prenatal genetic diagnosis using microarray analysis in fetuses with congenital heart defects. Prenat Diagn 2012; 32 (4) 376-382
• 2 Hillman SC, Pretlove S, Coomarasamy A , et al. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011; 37 (1) 6-14
• 3 Reddy UM, Page GP, Saade GR , et al; NICHD Stillbirth Collaborative Research Network. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 2012; 367 (23) 2185-2193
• 4 Fruhman G, Van den Veyver IB. Applications of array comparative genomic hybridization in obstetrics. Obstet Gynecol Clin North Am 2010; 37 (1) 71-85 , Table of Contents
• 5 Hillman SC, McMullan DJ, Silcock L, Maher ER, Kilby MD. How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings?. J Matern Fetal Neonatal Med 2014; 27 (7) 649-657
• 6 Wapner RJ, Martin CL, Levy B , et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367 (23) 2175-2184
• 7 Shaffer LG, Dabell MP, Rosenfeld JA , et al. Referral patterns for microarray testing in prenatal diagnosis. Prenat Diagn 2012; 32 (6) 611 DOI: 10.1002/pd.3856.
• 8 Menten B, Maas N, Thienpont B , et al. Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J Med Genet 2006; 43 (8) 625-633
• 9 Miller DT, Adam MP, Aradhya S , et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86 (5) 749-764
• 10 McGillivray G, Rosenfeld JA, McKinlay Gardner RJ, Gillam LH. Genetic counselling and ethical issues with chromosome microarray analysis in prenatal testing. Prenat Diagn 2012; 32 (4) 389-395
• 11 Novelli A, Grati FR, Ballarati L , et al. Microarray application in prenatal diagnosis: a position statement from the cytogenetics working group of the Italian Society of Human Genetics (SIGU), November 2011. Ultrasound Obstet Gynecol 2012; 39 (4) 384-388
• 12 Savage MS, Mourad MJ, Wapner RJ. Evolving applications of microarray analysis in prenatal diagnosis. Curr Opin Obstet Gynecol 2011; 23 (2) 103-108
• 13 Wapner RJ, Driscoll DA, Simpson JL. Integration of microarray technology into prenatal diagnosis: counselling issues generated during the NICHD clinical trial. Prenat Diagn 2012; 32 (4) 396-400
• 14 ACOG Committee Opinion No. ACOG Committee Opinion No. 446: array comparative genomic hybridization in prenatal diagnosis. Obstet Gynecol 2009; 114 (5) 1161-1163
• 15 Simpson LL. When a normal karyotype accompanies increased NT. In: MFM Consult. Contemporary OB/GYN; 2009
• 16 Lu X, Shaw CA, Patel A , et al. Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS ONE 2007; 2 (3) e327 DOI: 10.1371/journal.pone.0000327.
• 17 Lee CN, Lin SY, Lin CH, Shih JC, Lin TH, Su YN. Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG 2012; 119 (5) 614-625
• 18 Van den Veyver IB, Patel A, Shaw CA , et al. Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat Diagn 2009; 29 (1) 29-39
• 19 Coppinger J, Alliman S, Lamb AN, Torchia BS, Bejjani BA, Shaffer LG. Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray. Prenat Diagn 2009; 29 (12) 1156-1166
• 20 Fiorentino F, Napoletano S, Caiazzo F , et al. Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities. Eur J Hum Genet 2013; 21 (7) 725-730
• 21 Donnelly JC, Platt LD, Rebarber A, Zachary J, Grobman WA, Wapner RJ. Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstet Gynecol 2014; 124 (1) 83-90
• 22 Lund IC, Christensen R, Petersen OB, Vogel I, Vestergaard EM. Chromosomal microarray in fetuses with increased nuchal translucency. Ultrasound Obstet Gynecol 2015; 45 (1) 95-100
• 23 Leung TY, Vogel I, Lau TK , et al. Identification of submicroscopic chromosomal aberrations in fetuses with increased nuchal translucency and apparently normal karyotype. Ultrasound Obstet Gynecol 2011; 38 (3) 314-319
• 24 Shaffer LG, Rosenfeld JA, Dabell MP , et al. Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound. Prenat Diagn 2012; 32 (10) 986-995
• 25 Bakker M, Pajkrt E, Bilardo CM. Increased nuchal translucency with normal karyotype and anomaly scan: what next?. Best Pract Res Clin Obstet Gynaecol 2014; 28 (3) 355-366