Karyotyping has been the gold standard for prenatal chromosome analysis. The resolution should be higher by chromosome microarray analysis (CMA). The challenge lies in recognizing benign and pathogenic or clinically significant copy number variations (pCNV) and variations of unknown significance (VOUS). The aim was to evaluate the diagnostic yield and clinical utility of CMA, to stratify the CMA results in various prenatal referral groups and to accumulate Indian data of pCNVs and VOUS for further interpretation to assist defined genetic counseling.
Karyotyping and CMA were performed on consecutive referrals of 370 prenatal samples of amniotic fluid (n = 274) and chorionic villi (n = 96) from Indian pregnant women with high maternal age (n = 23), biochemical screen positive (n = 61), previous child abnormal (n = 59), abnormal fetal ultrasound (n = 205) and heterozygous parents (n = 22).
Results and Conclusion
The overall diagnostic yield of abnormal results was 5.40% by karyotyping and 9.18% by CMA. The highest percentage of pCNVs were found in the group with abnormal fetal ultrasound (5.40%) as compared to other groups, such as women with high maternal age (0.81%), biochemical screen positive (0.54%), previous abnormal offspring (0.81%) or heterozygous parents group (1.62%). Therefore, all women with abnormal fetal ultrasound must undergo CMA test for genotype–phenotype correlation. CMA detects known and rare deletion/duplication syndromes and characterizes marker chromosomes. Accumulation of CNV data will form an Indian Repository and also help to resolve the uncertainty of VOUS. Pretest and posttest genetic counseling is essential to convey benefits and limitations of CMA and help the patients to take informed decisions.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Lo JO, Shaffer BL, Feist CD, et al. Chromosomal microarray analysis and prenatal diagnosis. Obstet Gynecol Surv. 2014;69(10):613–21.
Joshi A, Lall M, Agarwal S, et al. Molecular characterization of supernumerary marker chromosomes found as unexpected chromosome abnormalities in nine prenatal and nine postnatal samples. Obstet Gynecol Int J. 2019;10(3):211–21.
Lawce HJ, Sanford J. Fluorescence in situ hybridization (FISH). In: Arsham MS, Barch MJ, Lawce HJ, editors. The AGT cytogenetics laboratory manual. 4th ed. Hobokon: Wiley; 2017. p. 717–36.
Lawce HJ, Sanford J. Prenatal chromosome diagnosis. In: Arsham MS, Barch MJ, Lawce HJ, editors. The AGT cytogenetics laboratory manual. 4th ed. Hobokon: Wiley; 2017. p. 173–209.
Lawce HJ. Chromosome stains. In: Arsham MS, Barch MJ, Lawce HJ, editors. The AGT cytogenetics laboratory manual. 4th ed. Hobokon: Wiley; 2017. p. 284–5.
ISCN. An International System for Human Cytogenomic Nomenclature (2016) Editors: Jean Mc Gowan-Jordan, Ottawa, Ont.; Annet Simons, Nijmegen; Michael Schmid, Wurzburg Reprint of Cytogenetic and Genome Research. 2016;149:1–2.
Nowakowska B. Clinical interpretation of copy number variants in the human genome. J Appl Genet. 2017;58(4):449–57.
Committee Opinion No. 682. American College of Obstetricians and Gynecologists. Microarrays and next-generation sequencing technologies: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol. 2016;128(6):e262–8.
Muys J, Blaumeiser B, Jacquemyn Y, et al. The BElgian PREnatal MicroArray (BEMAPRE) database: a systematic nationwide repository of fetal genomic aberrations. Prenat Diagn. 2018;38(13):1120–8.
Sansović I, Ivankov AM, Bobinec A, et al. Chromosomal microarray in clinical diagnosis: a study of 337 patients with congenital anomalies and developmental delays or intellectual disability. Croat Med J. 2017;58(3):231–8.
Kan AS, Lau ET, Tang WF, et al. Whole-genome array CGH evaluation for replacing prenatal karyotyping in Hong Kong. PLoS ONE. 2014;9(2):e87988.
Shaffer LG, Dabell MP, Fisher AJ, et al. Experience with microarray based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies. Prenat Diagn. 2012;32(10):976–85.
Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosome microarray is a first tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2011;86:749–64.
Armengol L, Nevado J, Serra-Juhe C, et al. Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis. Hum Genet. 2012;131:513–23.
Novelli A, Grati FR, Ballarati L, et al. Micro array 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):384–8.
Cheng SSW, Chan KYK, Leung KKP, et al. Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong. Am J Med Genet C. 2019;181(2):196–207.
Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–84.
Hay SB, Sahoo T, Travis MK, et al. ACOG and SMFM guidelines for prenatal diagnosis: is karyotyping really sufficient? Prenat Diagn. 2018;38(3):184–9.
Levy B, Wapner R. Prenatal diagnosis by chromosomal microarray analysis. Fertil Steril. 2018;109(2):201–12.
Goldenberg P. An update on common chromosome microdeletion and microduplication syndromes. Pediatr Ann. 2018;47(5):e198–203.
Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), (updated March 2020). World Wide Web. https://omim.org/. Accessed Jan–Feb 2020.
Burger NB, Bekker MN, de Groot CJM, et al. Why increased nuchal translucency is associated with congenital heart disease: a systematic review on genetic mechanisms. Prenat Diagn. 2015;35(6):517–28.
Xu W, Ahmad A, Dagenais S, et al. Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-34.3. Am J Med Genet A. 2012;158A:635–40.
Zepeda-Mendoza CJ, Morton CC. The iceberg under water: unexplored complexity of chromoanagenesis in congenital disorders. Am J Hum Genet. 2019;104(4):565–77.
https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=IT&Expert=261311. Accessed Jan–Feb 2020.
Martin CL, Ledbetter DH. Molecular cytogenetic analysis of telomere rearrangements. Curr Protoc Hum Genet. 2015;84:8.11.1–11.15.
Kroepfl T, Petek E, Schwarzbraun T, et al. Mental retardation in a girl with a subtelomeric deletion on chromosome 20q and complete deletion of the myelin transcription factor 1 gene (MYT1). Clin Genet. 2008;73:492–5.
Liehr T, Weise A. Frequency of small supernumerary marker chromosomes in prenatal, newborn, developmentally retarded and infertility diagnostics. Int J Mol Med. 2007;19:719–31.
Society for Maternal-Fetal Medicine, Dugoff L, Norton ME, et al. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2–9.
Wang J, Chen L, Zhou C, et al. Prospective chromosome analysis of 3429 amniocentesis samples in China using copy number variation sequencing. Am J Obstet Gynecol. 2018;219(3):287.e1–18.
We are thankful to Indian Council of Medical Research and Department of Health and research, New Delhi, for providing the research grant for this study (Project Code: 184.108.40.206/005). We also thank the patients, the referring clinicians, department of fetal medicine and the cytogenetics laboratory staff for their support.
This study was supported by funding grants from Indian Council of Medical Research/Department of Health Research (Project Code: 220.127.116.11/005).
Conflict of interest
The authors declare that there is no conflict of interests.
The study was performed in accordance with the ethical standards of the responsible committee on human experimentation and with Helsinki Declaration of 1975, as revised in 2008. The study was approved by the ethics committee of our institute (EC/11/12/435).
Informed consent was obtained from all the patients for being included in the study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dr. Lall Bajaj Meena Ph.D., Senior Consultant and Head, Clinical Cytogenetic Laboratory, Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi. She is also a Professor and teaching faculty for DNB programme and a Ph.D. guide. Agarwal Shruti Ph.D. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Paliwal Preeti Ph.D. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Saviour Pushpa Ph.D. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Joshi Anju M.Sc. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Joshi Arti M.Sc. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Mahajan Surbhi Ph.D. Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Bijarnia-Mahay Sunita MBBS, DNB, DCH Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. Puri Dua Ratna MBBS, MD, DM Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India. I. C. Verma MBBS, MRCP, DCH, MNAMS Institute of Medical Genetics and Genomics at Sir Ganga Ram Hospital, New Delhi, India.
About this article
Cite this article
Bajaj Lall, M., Agarwal, S., Paliwal, P. et al. Prenatal Diagnosis by Chromosome Microarray Analysis, An Indian Experience. J Obstet Gynecol India (2021). https://doi.org/10.1007/s13224-020-01413-6