Abstract
AMAÇ: İnsan genomunda bulunan 50 bazdan büyük değişikliklere ‘Kopya Sayısı Değişiklikleri’ (Copy Number Variations-CNV) adı verilmektedir. CNV’leri saptamak için rutinde mikrodizin (microarray) yöntemi kullanılmaktadır. Mikrodizin yöntemi zihinsel yetersizliğin, otizm spektrum bozukluğunun, çoklu doğumsal anomalilerin nedeninin saptanmasında ilk basamak testi olarak önerilmektedir. Çalışmanın amacı mikrodizin analizi ile saptanan değişikliklerin farklı filtreler ile değerlendirilip sonuçların karşılaştırılmasıdır.
GEREÇ VE YÖNTEM: Çalışmamız Sağlık Bakanlığı, Ankara Merkez Genetik Laboratuvarı bünyesinde farklı nöro-psikiyatrik bozukluk endikasyonlarla Affimetrix Cytoscan Optima çipleri ile mikrodizin yapılmış 500 hasta verisinin retrospektif değerlendirilmesi ile yapılmıştır. 500 hastanın verileri standart analiz yöntemi ile ve daha yüksek duyarlıkta analiz yapabilmek için 5 marker ve 1 kilobaz büyüklükteki değişiklikler incelenmiştir ve sonuçlar karşılaştırılmıştır.
BULGULAR: Standart analiz metodunda CNV saptanan 249 hastadan toplamda 313 CNV (%1.25) bulunmuş, daha yüksek çözünürlüklü analizde 362 hastadan 939 (%2.6) CNV tespit edilmiştir. Standart analizde 53 CNV saptanırken, yeni analiz metodunda 56 CNV saptanmıştır. Klinik anlamı bilinmeyen olarak sınıflanan CNV sayısı Standart yöntemde 105 iken, önerdiğimiz yeni analiz metodunda 318 olarak tespit edilmiştir. Ayrıca çalışmamız sırasında toplum frekansı %1’den büyük olan 12 CNV tespit edilmiştir.
SONUÇ: Sonuç olarak yeni yöntem testin tanı verme yüzdesini 10.7’den 11.3’e çıkarmış olmakla birlikte, klinik anlamı bilinmeyen ve olası yanlış pozitif sonuçları arttırmaktadır. Bu da analizi daha yüksek duyarlılıkla yapmakla birlikte, hem analiz süresini hem de testteki artefakt olarak adlandırılabilecek diğer sonuçların artmasına neden olmuştur. Ayrıca çalışmamızda Türk toplumunda göreceli olarak sık görülen 12 adet CNV bildirilmiştir.
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References
- Referans1. Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015 Mar;16(3):172-83. Referans2. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011 Jul;13(7):680-5. Referans3. Tan R, Wang Y, Kleinstein SE, Liu Y, Zhu X, Guo H, et al. An evaluation of copy number variation detection tools from whole-exome sequencing data. Human mutation. 2014 Jul;35(7):899-907. Referans4. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, 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 May 14;86(5):749-64. Referans5. Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med. 2009 Mar;11(3):139-46. Referans6. Robert Nussbaum RM, Huntington Willard. Thompson & Thompson Genetics in Medicine, 8th Edition: Elsevier; 2015. Referans7. Srebniak MI, Diderich KE, Govaerts LC, Joosten M, Riedijk S, Galjaard RJ, et al. Types of array findings detectable in cytogenetic diagnosis: a proposal for a generic classification. European journal of human genetics : EJHG. 2014 Jul;22(7):856-8. Referans8. Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, et al. Towards an evidence-based process for the clinical interpretation of copy number variation. Clinical genetics. 2012 May;81(5):403-12. Referans9. Ceylan AC, Citli S, Erdem HB, Sahin I, Acar Arslan E, Erdogan M. Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders. Mol Cytogenet. 2018;11:54. Referans10. Utine GE, Haliloglu G, Volkan-Salanci B, Cetinkaya A, Kiper PO, Alanay Y, et al. Etiological yield of SNP microarrays in idiopathic intellectual disability. Eur J Paediatr Neurol. 2014 May;18(3):327-37. Referans11. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011 Oct 25;77(17):1629-35. Referans12. Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Current opinion in genetics & development. 2012 Jun;22(3):229-37. Referans13. Nicholl J, Waters W, Mulley JC, Suwalski S, Brown S, Hull Y, et al. Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH. Pathology. 2014 Jan;46(1):41-5. Referans14. Devinsky O, Asato M, Camfield P, Geller E, Kanner AM, Keller S, et al. Delivery of epilepsy care to adults with intellectual and developmental disabilities. Neurology. 2015 Oct 27;85(17):1512-21. Referans15. Baker K, Costain G, Fung WL, Bassett AS. Chromosomal microarray analysis-a routine clinical genetic test for patients with schizophrenia. The lancet Psychiatry. 2014 Oct;1(5):329-31. Referans16. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet. 2009 Jul-Aug;52(4):161-9. Referans17. Hehir-Kwa JY, Pfundt R, Veltman JA. Exome sequencing and whole genome sequencing for the detection of copy number variation. Expert Rev Mol Diagn. 2015;15(8):1023-32. Referans18. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437-55. Referans19. Ozyilmaz B, Kirbiyik O, Koc A, Ozdemir TR, Kaya OO, Guvenc MS, et al. Experiences in microarray-based evaluation of developmental disabilities and congenital anomalies. Clin Genet. 2017 Oct;92(4):372-9. Referans20. Bahsi T, Unal A, Bakir A, Percin EF. THE 3rd W522X MUTATION IN EIF2AK3 GENE FROM TURKEY: A NEW PATIENT WITH WOLCOTT-RALLISON SYNDROME. Genet Couns. 2016;27(3):411-8.
Abstract
OBJECTIVE: Chromosome segment variations involving more than 50 bases are called Copy Number Variations (CNV). Chromosomal microarray method is used to detect CNVs in a routine practice. Chromosomal microarray analysis (CMA) is a first-tier test in the evaluation of individuals with intellectual disability and developmental delay with the diagnostic yield ranging from 5 to 20% varying based on population examined. The International Standard for the Consortium of Cytogenomic Array recommended CMA as a first-stage cytogenetic diagnostic test for patients with CA and ID / GDD. This study aimed to compare the standard and new high resolution analyze methods.
MATERIAL AND METHODS: Our study was carried out with retrospective evaluation of 500 patients with CMA with different indications with Affymetrix Cytoscan Optima chips in Ankara Atatürk Research and Education Hospital.
RESULTS: In the standard analysis method, 313 CNVs was detected at 298 patients. New analyze method detected 939 CNVs at 362 patients. Standard analysis method could not detect 3 pathogenic CNVs which were below 100-Kb. While in the standard analysis, 56 pathogenic CNVs was found in the new analysis method. The number of CNVs classified as unknown clinically was 105 in the standard method and 318 in the new analysis method. In addition, 12 CNVs with a frequency of more than 1% were detected in our study.
CONCLUSIONS: Although the new method has increased the diagnostic percentage of the test from 10.7 to 11.3, it increases the clinical significance and increases the false positive results. This has led to a higher sensitivity of the analysis, but has led to an increase in both the duration of the analysis and other results that can be called artifacts in the test. In addition, 10 CNVs which are relatively common in Turkish population have been reported in our study.
KEYWORDS: ,
Project Number
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References
- Referans1. Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015 Mar;16(3):172-83. Referans2. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance C. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011 Jul;13(7):680-5. Referans3. Tan R, Wang Y, Kleinstein SE, Liu Y, Zhu X, Guo H, et al. An evaluation of copy number variation detection tools from whole-exome sequencing data. Human mutation. 2014 Jul;35(7):899-907. Referans4. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, 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 May 14;86(5):749-64. Referans5. Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med. 2009 Mar;11(3):139-46. Referans6. Robert Nussbaum RM, Huntington Willard. Thompson & Thompson Genetics in Medicine, 8th Edition: Elsevier; 2015. Referans7. Srebniak MI, Diderich KE, Govaerts LC, Joosten M, Riedijk S, Galjaard RJ, et al. Types of array findings detectable in cytogenetic diagnosis: a proposal for a generic classification. European journal of human genetics : EJHG. 2014 Jul;22(7):856-8. Referans8. Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, et al. Towards an evidence-based process for the clinical interpretation of copy number variation. Clinical genetics. 2012 May;81(5):403-12. Referans9. Ceylan AC, Citli S, Erdem HB, Sahin I, Acar Arslan E, Erdogan M. Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders. Mol Cytogenet. 2018;11:54. Referans10. Utine GE, Haliloglu G, Volkan-Salanci B, Cetinkaya A, Kiper PO, Alanay Y, et al. Etiological yield of SNP microarrays in idiopathic intellectual disability. Eur J Paediatr Neurol. 2014 May;18(3):327-37. Referans11. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011 Oct 25;77(17):1629-35. Referans12. Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Current opinion in genetics & development. 2012 Jun;22(3):229-37. Referans13. Nicholl J, Waters W, Mulley JC, Suwalski S, Brown S, Hull Y, et al. Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH. Pathology. 2014 Jan;46(1):41-5. Referans14. Devinsky O, Asato M, Camfield P, Geller E, Kanner AM, Keller S, et al. Delivery of epilepsy care to adults with intellectual and developmental disabilities. Neurology. 2015 Oct 27;85(17):1512-21. Referans15. Baker K, Costain G, Fung WL, Bassett AS. Chromosomal microarray analysis-a routine clinical genetic test for patients with schizophrenia. The lancet Psychiatry. 2014 Oct;1(5):329-31. Referans16. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet. 2009 Jul-Aug;52(4):161-9. Referans17. Hehir-Kwa JY, Pfundt R, Veltman JA. Exome sequencing and whole genome sequencing for the detection of copy number variation. Expert Rev Mol Diagn. 2015;15(8):1023-32. Referans18. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437-55. Referans19. Ozyilmaz B, Kirbiyik O, Koc A, Ozdemir TR, Kaya OO, Guvenc MS, et al. Experiences in microarray-based evaluation of developmental disabilities and congenital anomalies. Clin Genet. 2017 Oct;92(4):372-9. Referans20. Bahsi T, Unal A, Bakir A, Percin EF. THE 3rd W522X MUTATION IN EIF2AK3 GENE FROM TURKEY: A NEW PATIENT WITH WOLCOTT-RALLISON SYNDROME. Genet Couns. 2016;27(3):411-8.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Articles |
| Authors | |
| Project Number | Yok |
| Publication Date | January 5, 2021 |
| Acceptance Date | February 24, 2020 |
| Published in Issue | Year 2021 Volume: 22 Issue: 1 |
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