The frequency of CNVs in a cohort population of consecutive fetuses with congenital anomalies after the termination of pregnancy

Gorazd Rudolf, Luca Lovrečić, Nataša Tul, Nataša Teran, Borut Peterlin, Gorazd Rudolf, Luca Lovrečić, Nataša Tul, Nataša Teran, Borut Peterlin

Abstract

Background: The implementation of molecular karyotyping has resulted in an improved diagnostic yield in the genetic diagnostics of congenital anomalies, detected prenatally or after the termination of pregnancy. However, the systematic epidemiologic ascertainment of copy number variations in the etiology of congenital anomalies has not yet been sufficiently explored.

Methods: Consecutive fetuses, altogether 204, with major single or multiple congenital anomalies were ascertained by using the SLOCAT registry for the period from 2011 to 2015. After excluding aneuploidies by using conventional karyotyping or Quantitative Fluorescence-Polymerase Chain Reaction, array comparative genomic hybridization was performed for the detection of copy number variations.

Results: We identified pathogenic or likely pathogenic copy number variations in 14 fetuses (6.8%); 2.9% in fetuses with isolated, and 3.9% in fetuses with multiple congenital anomalies. Additionally, aneuploidies and major structural chromosomal abnormalities were detected in 40.2%.

Conclusion: Our systematic approach of ascertaining congenital anomalies resulted in explaining the etiology of congenital anomalies in 47% of fetuses after the termination of pregnancy. By using array comparative genomic hybridization, we found that copy number variations represent an important part in the etiology of multiple, as well as isolated congenital anomalies, which indicates the importance of analyzing copy number variations in the diagnostic approach of fetuses with congenital anomalies after the termination of pregnancy.

Keywords: congenital anomalies; copy number variations; epidemiology; molecular karyotyping; termination of pregnancy.

Conflict of interest statement

This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. The authors stated that there are no conflicts of interest regarding the publication of this manuscript. The authors also state that they have had full control of all primary data and that they agree to allow the Journal to review their data if requested.

© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Figures

Figure 1
Figure 1
Representation of single CAs, according to the ICD10 nomenclature, in the study sample. CAs—congenital anomalies

References

    1. Babkina, N. , & Graham, J. M. Jr (2014). New genetic testing in prenatal diagnosis. Seminars in Fetal & Neonatal Medicine, 19, 214–219. 10.1016/j.siny.2013.10.005
    1. Béna, F. , Bruno, D. L. , Eriksson, M. , van Ravenswaaij‐Arts, C. , Stark, Z. , Dijkhuizen, T. , … Schoumans, J. (2013). Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics., 162B, 388–403. 10.1002/ajmg.b.32148
    1. Dabell, M. P. , Rosenfeld, J. A. , Bader, P. , Escobar, L. F. , El‐Khechen, D. , Vallee, S. E. , … Shaffer, L. G. (2013). Investigation of NRXN1 deletions: clinical and molecular characterization. American Journal of Medical Genetics. Part A, 161A, 717–731. 10.1002/ajmg.a.35780
    1. D'Amours, G. , Kibar, Z. , Mathonnet, G. , Fetni, R. , Tihy, F. , Désilets, V. , … Lemyre, E. (2012). Whole‐genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clinical Genetics, 81, 128–141. 10.1111/j.1399-0004.2011.01687.x
    1. Di Gregorio, E. , Gai, G. , Botta, G. , Calcia, A. , Pappi, P. , Talarico, F. , … Brussino, A. (2015). Array‐comparative genomic hybridization analysis in fetuses with major congenital malformations reveals that 24% of cases have pathogenic deletions/duplications. Cytogenet Genome Research, 147, 10–16. 10.1159/000442308
    1. Dolk, H. , Loane, M. , & Garne, E. (2010). The prevalence of congenital anomalies in Europe. Advances in Experimental Medicine and Biology, 686, 349–364. 10.1007/978-90-481-9485-8_20
    1. Gillentine, M. A. , & Schaaf, C. P. (2015). The human clinical phenotypes of altered CHRNA7 copy number. Biochemical Pharmacology, 97, 352–362. 10.1016/j.bcp.2015.06.012
    1. Jezela‐Stanek, A. , Kucharczyk, M. , Pelc, M. , Gutkowska, A. , & Krajewska‐Walasek, M. (2013). 1.15 Mb microdeletion in chromosome band 20p13 associated with moderate developmental delay‐additional case and data's review. American Journal of Medical Genetics. Part A, 161A, 172–178. 10.1002/ajmg.a.35654
    1. Le Caignec, C. , Boceno, M. , Saugier‐Veber, P. , Jacquemont, S. , Joubert, M. , David, A. , & , …, J. M. (2005). Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations. Journal of Medical Genetics 42, 121–128. 10.1136/jmg.2004.025478
    1. Lovrecic, L. , Remec, Z. , Volk, M. , Rudolf, G. , Writzl, K. , & Peterlin, B. (2016). Clinical utility of array comparative genomic hybridisation in prenatal setting. BMC Medical Genetics, 17, 81 10.1186/s12881-016-0345-8
    1. Miller, D. T. , Adam, M. P. , Aradhya, S. , Biesecker, L. G. , Brothman, A. R. , Carter, N. P. , … Ledbetter, D. H. (2010). Consensus statement: chromosomal microarray is a first‐tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics, 86, 749–764. 10.1016/j.ajhg.2010.04.006
    1. Nakane, T. , Kousuke, N. , Sonoko, H. , Yuko, K. , Sato, H. , Kubota, T. , & Sugita, K. (2013). 6p subtelomere deletion with congenital glaucoma, severe mental retardation, and growth impairment. Pediatrics International, 55, 376–381. 10.1111/j.1442-200X.2012.03729.x
    1. Nicolaides, K. H. , Snijders, R. J. , Gosden, C. M. , Berry, C. , & Campbell, S. (1992). Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet, 340, 704–707.
    1. Ounap, K. , Ilus, T. , & Bartsch, O. (2005). A girl with inverted triplication of chromosome 3q25.3 –> q29 and multiple congenital anomalies consistent with 3q duplication syndrome. American Journal of Medical Genetics. Part A, 134, 434–438. 10.1002/ajmg.a.30134
    1. Rodríguez, L. , Bhatt, S. S. , García‐Castro, M. , Plasencia, A. , Fernández‐Toral, J. , Abarca, E. , … Liehr, T. (2014). A unique case of a discontinuous duplication 3q26.1‐3q28 resulting from a segregation error of a maternal complex chromosomal rearrangement involving an insertion and an inversion. Gene, 535, 165–169. 10.1016/j.gene.2013.11.041
    1. Sebold, C. D. , Romie, S. , Szymanska, J. , Torres‐Martinez, W. , Thurston, V. , Muesing, C. , & Vance, G. H. (2005). Partial trisomy 2q: report of a patient with dup (2)(q33.1q35). American Journal of Medical Genetics. Part A, 134A, 80–83. 10.1002/ajmg.a.30463
    1. Shaffer, L. G. , Dabell, M. P. , Fisher, A. J. , Coppinger, J. , Bandholz, A. M. , Ellison, J. W. , … Rosenfeld, J. A. (2012). Experience with microarray‐based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies. Prenatal Diagnosis, 32, 976–985. 10.1002/pd.3945
    1. South, S.T. , Lee, C. , Lamb, A. N. , Higgins, A. W. , & Kearney, H. M. ; Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee . (2013). ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genetics in Medicine 15, 901–9. 10.1038/gim.2013.129
    1. Srebniak, M. I. , Didreich, K. E. , Joosten, M. , Govaerts, L. C. , Knijnenburg, J. , de Vries, F. A. , … Van Opstal, D. (2016). Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. European Journal of Human Genetics, 24, 645–651. 10.1038/ejhg.2015.193
    1. Staebler, M. , Donner, C. , Van Regemorter, N. , Duprez, L. , De Maertelaer, V. , Devreker, F. , & Avni, F. (2005). Should determination of the karyotype be systematic for all malformations detected by obstetrical ultrasound? Prenatal Diagnosis, 25, 567–573. 10.1002/pd.1187
    1. Starr, L. J. , Truemper, E. J. , Pickering, D. L. , Sanger, W. G. , & Olney, A. H. (2014). Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications. American Journal of Medical Genetics. Part A, 164A, 2020–2024. 10.1002/ajmg.a.34020
    1. Szczałuba, K. , Nowakowska, B. , Sobecka, K. , Smyk, M. , Castaneda, J. , Klapecki, J. , … Demkow, U. (2016). Application of Array Comparative Genomic Hybridization in Newborns with Multiple Congenital Anomalies. Advances in Experimental Medicine and Biology, 912, 1–9. 10.1007/5584_2016_235
    1. Usui, D. , Shimada, S. , Shimojima, K. , Sugawara, M. , Kawasaki, H. , Shigematu, H. , … Yamamoto, T. (2013). Interstitial duplication of 2q32.1‐q33.3 in a patient with epilepsy, developmental delay, and autistic behavior. American Journal of Medical Genetics. Part A, 161A, 1078–1084. 10.1002/ajmg.a.35679
    1. Valduga, M. , Philippe, C. , Bach Segura, P. , Thiebaugeorges, O. , Miton, A. , Beri, M. , … Jonveaux, P. (2010). A retrospective study by oligonucleotide array‐CGH analysis in 50 fetuses with multiple malformations. Prenatal Diagnosis, 30, 333–341. 10.1002/pd.2460
    1. Vialard, F. , Molina Gomes, D. , Leroy, B. , Quarello, E. , Escalona, A. , Le Sciellour, C. , … Selva, J. (2009). Array comparative genomic hybridization in prenatal diagnosis: another experience. Fetal Diagnosis and Therapy, 25, 277–284. 10.1159/000224112
    1. Viñas‐Jornet, M. , Esteba‐Castillo, S. , Gabau, E. , Ribas‐Vidal, N. , Baena, N. , San, J. , … Guitart, M. (2014). A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion. Molecular Genetics and Genomic Medicine, 2, 512–521. 10.1002/mgg3.105
    1. Wapner, R. J. , Martin, C. L. , Levy, B. , Ballif, B. C. , Eng, C. M. , Zachary, J. M. , … Jackson, L. (2012). Chromosomal microarray versus karyotyping for prenatal diagnosis. New England Journal of Medicine, 367, 2175–2178. 10.1056/NEJMoa1203382
    1. Wong, S. L. , Chou, H. H. , Chao, C. N. , Leung, J. H. , Chen, Y. H. , & Hsu, C. D. (2015). Distal 10q trisomy with copy number gain in chromosome region 10q23.1‐10q25.1: the Wnt signaling pathway is the most pertinent to the gene content in the region of copy number gain: a case report. BMC Research Notes 8, 250 10.1186/s13104-015-1213-x

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