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Prenatal Genetic Testing With Chromosomal Microarray Analysis Identifies Major Risk Variants for Schizophrenia and Other Later-Onset Disorders

2013; American Psychiatric Association; Volume: 170; Issue: 12 Linguagem: Inglês

10.1176/appi.ajp.2013.13070880

1535-7228

Gregory Costain, Donna M. McDonald‐McGinn, Anne S. Bassett,

Congenital heart defects research

Back to table of contents Previous article Next article Communications and UpdatesFull AccessPrenatal Genetic Testing With Chromosomal Microarray Analysis Identifies Major Risk Variants for Schizophrenia and Other Later-Onset DisordersGregory Costain, Ph.D., Donna M. McDonald-McGinn, M.S., C.G.C., and Anne S. Bassett, M.D., F.R.C.P.C.Gregory Costain, Ph.D., Donna M. McDonald-McGinn, M.S., C.G.C., and Anne S. Bassett, M.D., F.R.C.P.C.Published Online:1 Dec 2013https://doi.org/10.1176/appi.ajp.2013.13070880AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Recent studies (1, 2) have demonstrated the advantages of genome-wide chromosomal microarray analysis over karyotype for the prenatal detection of pathogenic copy number variants. Chromosomal microarray analysis may soon become the standard of care in the prenatal setting (1, 2). Not discussed is the potential for later-onset phenotypes of findings identified in utero and the resultant ethical and societal challenges. For example, 22q11.2 deletions are associated with a 20%−25% risk of schizophrenia and more than 60% lifetime risk for any treatable psychiatric disorder (3). Other large (e.g., >500 kb) copy number variants are now known to be enriched in diverse neuropsychiatric diseases and are absent or very uncommon in control populations (4). To date, schizophrenia is the best studied later-onset disease for which there are replicated associations of moderate or greater effect size with specific copy number variants (5, 6). We therefore quantified the extent to which clinically significant copy number variants reported to patients in a study of prenatal chromosomal microarray analysis (1) were also known to be associated with greater risk for schizophrenia.In this largest study to date (1), established schizophrenia risk variants accounted for 49% (17 of 35) of the copy number variants of definite clinical significance discovered in 3,822 karyotypically normal pregnancies. These included a 1q21.1 deletion, a 15q13.3 deletion, four 17q12 deletions, and 11 typical 22q11.2 deletions (6, 7). All but one were de novo mutations. Fourteen (23%) of 61 additional copy number variants reported to patients as having the potential for clinical significance are associated with schizophrenia: three 1q21.1 duplications, one 2q13 duplication, one 15q11-q13 duplication, four 16p13.11 duplications, and five atypical 22q11.2 deletions (5–7). Thus, at a minimum, one in every 124 prenatal samples (31/3,822) sent for clinical chromosomal microarray analysis would be reported as having a clinically significant finding that might also be considered a schizophrenia risk variant. Notably, a typical 22q11.2 deletion was found in one in every 347 prenatal samples (including one in every 1,022 samples with no anomaly on ultrasonography). The true incidence of 22q11.2 deletions in live births remains unknown (8). Analyses of data from other smaller studies of prenatal chromosomal microarray analysis yielded comparable results (data not shown).Prenatal detection of copy number variants with attendant elevated risk for schizophrenia and multiple other conditions is increasingly a reality. Demand for early interventions to reduce such risks (9) is likely to increase. There are associated ethical and societal implications that have been previously considered mostly in the abstract for later-onset diseases like schizophrenia. The opinions of patients, families, psychiatrists, and other key stakeholders are largely unknown. Lessons learned from now-familiar scenarios in prenatal genetic testing, such as the association of Alzheimer's disease with trisomy 21, will help guide our approach to prenatal testing using chromosomal microarray analysis.From the Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario; the Clinical Genetics Center and the 22q and You Center, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and the Department of Psychiatry, University of Toronto, Ontario.The authors report no financial relationships with commercial interests.References1 Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L: Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367:2175–2184Crossref, Medline, Google Scholar2 Fiorentino F, Napoletano S, Caiazzo F, Sessa M, Bono S, Spizzichino L, Gordon A, Nuccitelli A, Rizzo G, Baldi M: 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; 21:725–730Crossref, Medline, Google Scholar3 Fung WL, McEvilly R, Fong J, Silversides CK, Chow EWC, Bassett AS: Elevated prevalence of generalized anxiety disorder in adults with 22q11.2 deletion syndrome. Am J Psychiatry 2010; 167:998Link, Google Scholar4 Lee C, Scherer SW: The clinical context of copy number variation in the human genome. Expert Rev Mol Med 2010; 12:e8Crossref, Medline, Google Scholar5 Costain G, Lionel AC, Merico D, Forsythe P, Russell K, Lowther C, Yuen T, Husted J, Stavropoulos DJ, Speevak M, Chow EW, Marshall CR, Scherer SW, Bassett AS: Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. Hum Mol Genet (Epub ahead of print, June 27, 2013)Google Scholar6 Costain G, Bassett AS: Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era. Appl Clin Genet 2012; 5:1–18Medline, Google Scholar7 Bassett AS, Scherer SW, Brzustowicz LM: Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry 2010; 167:899–914Link, Google Scholar8 McDonald-McGinn DM, Sullivan KE: Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore) 2011; 90:1–18Crossref, Medline, Google Scholar9 Ross RG, Hunter SK, McCarthy L, Beuler J, Hutchison AK, Wagner BD, Leonard S, Stevens KE, Freedman R: Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. Am J Psychiatry 2013; 170:290–298Link, Google Scholar FiguresReferencesCited byDetailsCited byGenes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and PsychopathologySébastien Jacquemont, M.D., Guillaume Huguet, Ph.D., Marieke Klein, Ph.D., Samuel J.R.A. Chawner, Ph.D., Kirsten A. Donald, M.D., Ph.D., Marianne B.M. van den Bree, Ph.D., Jonathan Sebat, Ph.D., David H. Ledbetter, Ph.D., John N. Constantino, M.D., Rachel K. Earl, Ph.D., Donna M. McDonald-McGinn, M.S., L.C.G.C., Therese van Amelsvoort, M.D., Ph.D., Ann Swillen, Ph.D., Anne H. O'Donnell-Luria, David C. Glahn, Ph.D.,Laura Almasy, Ph.D., Evan E. Eichler, Ph.D., Stephen W. Scherer, Ph.D., Elise Robinson, Ph.D., Anne S. Bassett, M.D., Christa Lese Martin, Ph.D., Brenda Finucane, M.S., Jacob A.S. Vorstman, M.D., Ph.D., Carrie E. Bearden, Ph.D., Raquel E. Gur, M.D., Ph.D., 3 March 2022 | American Journal of Psychiatry, Vol. 179, No. 3Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion3 February 2020 | Molecular Psychiatry, Vol. 26, No. 8Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion SyndromeAnne S. Bassett, M.D., Chelsea Lowther, B.Sc., Daniele Merico, Ph.D., Gregory Costain, M.D., Ph.D., Eva W. C. Chow, M.D., Therese van Amelsvoort, M.D., Ph.D., Donna McDonald-McGinn, M.Sc., Raquel E. Gur, M.D., Ph.D., Ann Swillen, Ph.D., Marianne Van den Bree, Ph.D., Kieran Murphy, M.D., Ph.D., Doron Gothelf, M.D., Carrie E. Bearden, Ph.D., Stephan Eliez, M.D., Wendy Kates, Ph.D., Nicole Philip, M.D., Vandana Sashi, M.D., Linda Campbell, Ph.D., Jacob Vorstman, M.D., Ph.D., Joseph Cubells, M.D., Ph.D., Gabriela M. Repetto, M.D., Tony Simon, Ph.D., Erik Boot, M.D., Ph.D., Tracy Heung, M.A., Rens Evers, M.D., Ph.D., Claudia Vingerhoets, M.Sc., Esther van Duin, M.Sc., Elaine Zackai, M.D., Elfi Vergaelen, M.Sc., Koen Devriendt, M.D., Joris R. Vermeesch, Ph.D., Michael Owen, M.D., Ph.D., Clodagh Murphy, Ph.D., Elena Michaelovosky, Ph.D., Leila Kushan, M.Sc., Maude Schneider, M.Sc., Wanda Fremont, M.D., Tiffany Busa, M.D., Stephen Hooper, Ph.D., Kathryn McCabe, Ph.D., Sasja Duijff, Ph.D., Karin Isaev, B.Sc., Giovanna Pellecchia, Ph.D., John Wei, Ph.D., Matthew J. Gazzellone, M.Sc., Stephen W. Scherer, Ph.D., Beverly S. Emanuel, Ph.D., Tingwei Guo, Ph.D., Bernice E. Morrow, Ph.D., Christian R. Marshall, Ph.D., 28 July 2017 | American Journal of Psychiatry, Vol. 174, No. 11Prenatal Diagnosis, Vol. 37, No. 1Prenatal Diagnosis, Vol. 37, No. 1Prenatal Diagnosis, Vol. 37, No. 4Frontiers in Molecular Neuroscience, Vol. 10Genetics in Medicine, Vol. 18, No. 4Developmental trajectories in 22q11.2 deletion syndrome18 May 2015 | American Journal of Medical Genetics Part C: Seminars in Medical Genetics, Vol. 169, No. 2Journal of Genetic Counseling, Vol. 24, No. 5Biological Psychiatry, Vol. 77, No. 2Genetics in Medicine, Vol. 17, No. 8Genetics in Medicine, Vol. 17, No. 2Frontiers in Neurology, Vol. 5 Volume 170Issue 12 December 2013Pages 1498-1498 Metrics PDF download History Accepted 1 October 2013 Published online 1 December 2013 Published in print 1 December 2013