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NORMAL KARYOTİPLİ PATOLOJİK ULTRASON BULGUSU OLAN FETUSLARDA MLPA (MULTİPLEX LİGATİON-DEPENDENT PROBE AMPLİFİCATİON) UYGULAMALARI

Year 2019, Volume: 82 Issue: 1, 5 - 11, 28.03.2019

Güven Toksoy Birsen Karaman Zehra Oya Uyguner Kader Yılmaz Recep Has Hülya Kayserili Peter Mıny Seher Başaran

Abstract

Objective/Material and Method: Cryptic chromosomal imbalances contribute significantly to the etiology of multiple congenital anomalies with or without mental retardation (MCA/MR). Current approaches in prenatal diagnosis include targeted high resolution analyses by MLPA and some microarray platforms or a genomewide screening at maximal resolution using oligonucleotide or SNP arrays. The major disadvantages of the latter approach are cost and the inadvertent detection of copy number variation of unknown clinical significance. 

In this prospective work, fetal DNA samples from 66 fetuses who had pathological antenatal ultrasonography findings with normal karyotype and Multiprobe T-FISH results were tested using commercially available targeted MLPA probe-sets to compare the efficacy and the impact of MLPA testing at prenatal setting.

Results: Three submicroscopic deletions (3.66; 4.5%) were detected in the cohort. Two of them were de novo deletions, 18ptel and 7q11.23. The third finding was a 75 kb duplication at 18q, which was maternally inherited and probably a benign copy number variation unrelated to the pathological ultarsonography findings.

Conclusion: The observed detection rate by MLPA testing can be considered within the expected range. Furthermore, benign copy number variation was identified with the targeted diagnostic approach as an unexpected finding. This study shows that MLPA is a practical and cost-effective technique to investigate submicroscobic chromosomal aberrations in fetuses.


Keywords

MLPA subtelomerik değişimler doğum öncesi tanı mikrodelesyon/mikroduplikasyon

References

  • 1. Nussbaum RL, McInnes RR, Willard HF, Hamosh A. Principles of clinical cytogenetics, Thompson&Thompson Genetics in Medicine, Saunders, Elsevier. Philadelphia, PA, 7th ed., 2007;59-113.
  • 2. Adams-Chapman I, Hansen NI, Shankaran S, Bell EF, Boghossian NS, Murray JC, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Ten-year review of major birth defect s in VLBW infants. Pediatrics 2013;132(1):49-61.
  • 3. Eydoux P, Choiset A, Le Porrier N, Thépot F, Szpiro-Tapia S, Alliet J, et al. Chromosomal prenatal diagnosis: study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diagn 1989;9(4):255-69.
  • 4. Daniel A, Athayde N, Ogle R, George AM, Michael J, Pertile MD, et al. Prospective ranking of the sonographic markers for aneuploidy: data of 2143 prenatal cytogenetic diagnoses referred for abnormalities on ultrasound. Aust N Z J Obstet Gynaecol 2003;43(1):16-26.
  • 5. Zhang L, Zhang XH, Liang MY, Ren MH. Prenatal cytogenetic diagnosis study of 2782 cases of high-risk pregnant women. Chin Med J (Engl) 2010;123(4):423-30.
  • 6. Lichtenbelt KD, Alizadeh BZ, Scheffer PG, Stoutenbeek P, Schielen PC, Page-Christiaens LC, et al. Trends in the utilization of invasive prenatal diagnosis in The Netherlands during 2000-2009. Prenat Diagn 2011;31(8):765-72.
  • 7. D’Amours G, Kibar Z, Mathonnet G, Fetni R, Tihy F, De´silets V, et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet 2012;81(2):128-41.
  • 8. Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 1995;9(2):132-40.
  • 9. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354(9191):1676-81.
  • 10. Rossi E, Piccini F, Zollino M, Neri G, Caselli D, Tenconi R, et al. Cryptic telomeric rearrangements in subjects with mental retardation associated with dysmorphism and congenital malformations. J Med Genet 2001;38(6):417-20.
  • 11. Baker E, Hinton L, Callen DF, Altree M, Dobbie A, Eyre HJ, et al. Study of 250 children with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies. Am J Med Genet 2002;107(4):285-93.
  • 12. Gignac J, Danis K, Tihy F, Lemyre E. Prenatal detection of subtelomeric rearrangements by multi-subtelomere FISH in a cohort of fetuses with major malformations. Am J Med Genet A 2006;140(24):2768-75.
  • 13. Kjaergaard S, Sundberg K, Jørgensen FS, Rohde MD, Lind AM, Gerdes T, et al. Diagnostic yield by supplementing prenatal metaphase karyotyping with MLPA for microdeletion syndromes and subtelomere imbalances. Prenat Diagn 2010;30(10):995-9.
  • 14. Shaffer LG, Bejjani BA. A cytogeneticist’s perspective on genomic microarrays. Hum Reprod Update 2004;10(3):221-6.
  • 15. Shaffer LG, Coppinger J, Alliman S, Torchia BA, Theisen A, Ballif BC, et al. Comparison of microarray-based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenat Diagn 2008;28(9):789-95.
  • 16. Schou KV, Kirchhoff M, Nygaard U, Jorgersen C, Sundberg K. Increased nuchal translucency with normal karyotype: afollow-up study of 100 cases supplemented with CGH and MLPA analyses. Ultrasound Obstet Gynecol 2009;34(6):618-22.
  • 17. Schaffer LG, Bejjani BA. Medical applications of array CGH and the transformation of clinical cytogenetics. Cytogenet Genome Res 2006;115(3-4):303-9.
  • 18. Vialard F, Molina Gomes D, Leroy B, Quarello E, Escalona A, Le Sciellour C, et al. Array comparative genomic hybridization in prenatal diagnosis: another experience. Fetal Diagn Ther 2009;25(2):277-84.
  • 19. Thuresson AC, Bondeson ML, Edeby C, Ellis P, Langford C, Dumanski JP, et al. Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation. Cytogenet Genome Res 2007;118(1):1-7.
  • 20. Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 2008;124(1):1-17.
  • 21. Engels H, Wohlleber E, Zink A, Hoyer J, Ludwig KU, Brockschmidt FF, et al. A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 2009;17(12):1592-9.
  • 22. Gross SJ, Bajaj K, Garry D, Klugman S, Karpel BM, Marie Roe A, et al. Rapid and novel prenatal molecular assay for detecting aneuploidies and microdeletion syndromes. Prenat Diagn 2011;31(3):259-66.
  • 23. Mademont-Soler I, Morales C, Bruguera C, Madrigal I,Clusellas N, Margarit E, et al. Subtelomeric MLPA: is it really useful in prenatal diagnosis? Prenat Diagn 2010;30(12-13):1165-9.
  • 24. Goumy C, Gouas L, Pebrel-Richard C, Véronèse L, Eymard-Pierre E, Debost-Legrand A, et al. Prenatal detection of cryptic rearrangements by multiplex ligation probe amplification in fetuses with ultrasound abnormalities. Genet Med 2010;12(6):376-80.
  • 25. Kleeman L, Bianchi DW, Shaffer LG, Rorem E, Cowan J, Craigo SD, et al. Use of array comparative genomic hybridization for prenatal diagnosis of fetuses with sonographic anomalies and normal metaphase karyotype. Prenat Diagn 2009;29(13):1213-7.
  • 26. Kontos H, Manolakos E, Malligiannis P, Plachouras N, Ploumis N, Mihalatos M, et al. Prenatal diagnosis of a fetus with 7q11.23 deletion detected by multiplex ligation-dependent probe amplification (MLPA) screening. Prenat Diagn 2008;28(6):556-8.
  • 27. Van den Veyver IB, Patel A, Shaw CA, Pursley AN, Kang SH, Simovich MJ, et al. Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat Diagn 2009;29(1):29-39.
  • 28. Konialis C, Hagnefelt B, Sevastidou S, Karapanou S, Pispili K, Markaki A, et al. Uncovering recurrent microdeletion syndromes and subtelomeric deletions/duplications through non-selective application of a MLPA based extended prenatal panel in routine prenatal diagnosis. Prenat Diagn 2011;31(6):571-7.
  • 29. Krzeminska D, Steinfeld C, Cloez JL, Vibert M, Chery M, Menziesat D, et al. Prenatal diagnosis of Williams syndrome based on ultrasound signs. Prenat Diagn 2009;29(7):710-2.
  • 30. Popowski T, Vialard F, Leroy B, Bault JP, Molina-Gomes D. Williams-Beuren syndrome: the prenatal phenotype. Am J Obstet Gynecol 2011;205(6):e6-8.
  • 31. Lee CN, Lin SY, Lin CH, Shih JC, Lin TH, Su YN. Clinical utility of array comparative genomic hybridization for prenatal diagnosis:a cohort study of 3171 pregnancies. BJOG 2012; 119(5):614–25.
  • 32. Johnson G, Bachman R. A 46,XY,del(18)(pter-p1100:) cebocephalic child from a 46,XX,t(12;18)(18pter-18p1100::12qter-12pter) normal parent. Hum Genet 1976;34(1):103-6.
  • 33. Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 2000;25(2):205-8.
  • 34. Database of genomic variation, “A curated catalogue of human genomic structural variation”, 2018/09/21, Available from: http://dgv.tcag.ca/dgv/app/variant?id= dgv3407n100&ref=GRCh37/hg19
  • 35. DECIPHER, “Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources”, 2018/09/21 Available from: https://decipher.sanger.ac.uk/patient/291627#genotype/cnv/67391/browser/18:76996166-77946488
  • 36. Varon R, Gooding R, Steglich C, Marns L, Tang H, Angelicheva D et al. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet 2003;35(2):185-9.
  • 37. Choi JS, Lee WJ, Baik SH, Yoon HK, Lee KH, Kim YH. Array CGH reveals genomic aberrations in human emphysema. Lung 2009;187(3):165-72.

APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE

Year 2019, Volume: 82 Issue: 1, 5 - 11, 28.03.2019

Güven Toksoy Birsen Karaman Zehra Oya Uyguner Kader Yılmaz Recep Has Hülya Kayserili Peter Mıny Seher Başaran

Abstract

Objective/Material and Method: Cryptic chromosomal imbalances contribute significantly to the etiology of multiple congenital anomalies with or without mental retardation (MCA/MR). Current approaches in prenatal diagnosis include targeted high resolution analyses by MLPA and some microarray platforms or a genomewide screening at maximal resolution using oligonucleotide or SNP arrays. The major disadvantages of the latter approach are cost and the inadvertent detection of copy number variation of unknown clinical significance. 

In this prospective work, fetal DNA samples from 66 fetuses who had pathological antenatal ultrasonography findings with normal karyotype and Multiprobe T-FISH results were tested using commercially available targeted MLPA probe-sets to compare the efficacy and the impact of MLPA testing at prenatal setting.

Results: Three submicroscopic deletions (3.66; 4.5%) were detected in the cohort. Two of them were de novo deletions, 18ptel and 7q11.23. The third finding was a 75 kb duplication at 18q, which was maternally inherited and probably a benign copy number variation unrelated to the pathological ultarsonography findings.

Conclusion: The observed detection rate by MLPA testing can be considered within the expected range. Furthermore, benign copy number variation was identified with the targeted diagnostic approach as an unexpected finding. This study shows that MLPA is a practical and cost-effective technique to investigate submicroscobic chromosomal aberrations in fetuses.


Keywords

MLPA subtelomeric anomalies prenatal diagnosis microdeletion/microduplication

References

  • 1. Nussbaum RL, McInnes RR, Willard HF, Hamosh A. Principles of clinical cytogenetics, Thompson&Thompson Genetics in Medicine, Saunders, Elsevier. Philadelphia, PA, 7th ed., 2007;59-113.
  • 2. Adams-Chapman I, Hansen NI, Shankaran S, Bell EF, Boghossian NS, Murray JC, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Ten-year review of major birth defect s in VLBW infants. Pediatrics 2013;132(1):49-61.
  • 3. Eydoux P, Choiset A, Le Porrier N, Thépot F, Szpiro-Tapia S, Alliet J, et al. Chromosomal prenatal diagnosis: study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diagn 1989;9(4):255-69.
  • 4. Daniel A, Athayde N, Ogle R, George AM, Michael J, Pertile MD, et al. Prospective ranking of the sonographic markers for aneuploidy: data of 2143 prenatal cytogenetic diagnoses referred for abnormalities on ultrasound. Aust N Z J Obstet Gynaecol 2003;43(1):16-26.
  • 5. Zhang L, Zhang XH, Liang MY, Ren MH. Prenatal cytogenetic diagnosis study of 2782 cases of high-risk pregnant women. Chin Med J (Engl) 2010;123(4):423-30.
  • 6. Lichtenbelt KD, Alizadeh BZ, Scheffer PG, Stoutenbeek P, Schielen PC, Page-Christiaens LC, et al. Trends in the utilization of invasive prenatal diagnosis in The Netherlands during 2000-2009. Prenat Diagn 2011;31(8):765-72.
  • 7. D’Amours G, Kibar Z, Mathonnet G, Fetni R, Tihy F, De´silets V, et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet 2012;81(2):128-41.
  • 8. Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 1995;9(2):132-40.
  • 9. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354(9191):1676-81.
  • 10. Rossi E, Piccini F, Zollino M, Neri G, Caselli D, Tenconi R, et al. Cryptic telomeric rearrangements in subjects with mental retardation associated with dysmorphism and congenital malformations. J Med Genet 2001;38(6):417-20.
  • 11. Baker E, Hinton L, Callen DF, Altree M, Dobbie A, Eyre HJ, et al. Study of 250 children with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies. Am J Med Genet 2002;107(4):285-93.
  • 12. Gignac J, Danis K, Tihy F, Lemyre E. Prenatal detection of subtelomeric rearrangements by multi-subtelomere FISH in a cohort of fetuses with major malformations. Am J Med Genet A 2006;140(24):2768-75.
  • 13. Kjaergaard S, Sundberg K, Jørgensen FS, Rohde MD, Lind AM, Gerdes T, et al. Diagnostic yield by supplementing prenatal metaphase karyotyping with MLPA for microdeletion syndromes and subtelomere imbalances. Prenat Diagn 2010;30(10):995-9.
  • 14. Shaffer LG, Bejjani BA. A cytogeneticist’s perspective on genomic microarrays. Hum Reprod Update 2004;10(3):221-6.
  • 15. Shaffer LG, Coppinger J, Alliman S, Torchia BA, Theisen A, Ballif BC, et al. Comparison of microarray-based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenat Diagn 2008;28(9):789-95.
  • 16. Schou KV, Kirchhoff M, Nygaard U, Jorgersen C, Sundberg K. Increased nuchal translucency with normal karyotype: afollow-up study of 100 cases supplemented with CGH and MLPA analyses. Ultrasound Obstet Gynecol 2009;34(6):618-22.
  • 17. Schaffer LG, Bejjani BA. Medical applications of array CGH and the transformation of clinical cytogenetics. Cytogenet Genome Res 2006;115(3-4):303-9.
  • 18. Vialard F, Molina Gomes D, Leroy B, Quarello E, Escalona A, Le Sciellour C, et al. Array comparative genomic hybridization in prenatal diagnosis: another experience. Fetal Diagn Ther 2009;25(2):277-84.
  • 19. Thuresson AC, Bondeson ML, Edeby C, Ellis P, Langford C, Dumanski JP, et al. Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation. Cytogenet Genome Res 2007;118(1):1-7.
  • 20. Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 2008;124(1):1-17.
  • 21. Engels H, Wohlleber E, Zink A, Hoyer J, Ludwig KU, Brockschmidt FF, et al. A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 2009;17(12):1592-9.
  • 22. Gross SJ, Bajaj K, Garry D, Klugman S, Karpel BM, Marie Roe A, et al. Rapid and novel prenatal molecular assay for detecting aneuploidies and microdeletion syndromes. Prenat Diagn 2011;31(3):259-66.
  • 23. Mademont-Soler I, Morales C, Bruguera C, Madrigal I,Clusellas N, Margarit E, et al. Subtelomeric MLPA: is it really useful in prenatal diagnosis? Prenat Diagn 2010;30(12-13):1165-9.
  • 24. Goumy C, Gouas L, Pebrel-Richard C, Véronèse L, Eymard-Pierre E, Debost-Legrand A, et al. Prenatal detection of cryptic rearrangements by multiplex ligation probe amplification in fetuses with ultrasound abnormalities. Genet Med 2010;12(6):376-80.
  • 25. Kleeman L, Bianchi DW, Shaffer LG, Rorem E, Cowan J, Craigo SD, et al. Use of array comparative genomic hybridization for prenatal diagnosis of fetuses with sonographic anomalies and normal metaphase karyotype. Prenat Diagn 2009;29(13):1213-7.
  • 26. Kontos H, Manolakos E, Malligiannis P, Plachouras N, Ploumis N, Mihalatos M, et al. Prenatal diagnosis of a fetus with 7q11.23 deletion detected by multiplex ligation-dependent probe amplification (MLPA) screening. Prenat Diagn 2008;28(6):556-8.
  • 27. Van den Veyver IB, Patel A, Shaw CA, Pursley AN, Kang SH, Simovich MJ, et al. Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat Diagn 2009;29(1):29-39.
  • 28. Konialis C, Hagnefelt B, Sevastidou S, Karapanou S, Pispili K, Markaki A, et al. Uncovering recurrent microdeletion syndromes and subtelomeric deletions/duplications through non-selective application of a MLPA based extended prenatal panel in routine prenatal diagnosis. Prenat Diagn 2011;31(6):571-7.
  • 29. Krzeminska D, Steinfeld C, Cloez JL, Vibert M, Chery M, Menziesat D, et al. Prenatal diagnosis of Williams syndrome based on ultrasound signs. Prenat Diagn 2009;29(7):710-2.
  • 30. Popowski T, Vialard F, Leroy B, Bault JP, Molina-Gomes D. Williams-Beuren syndrome: the prenatal phenotype. Am J Obstet Gynecol 2011;205(6):e6-8.
  • 31. Lee CN, Lin SY, Lin CH, Shih JC, Lin TH, Su YN. Clinical utility of array comparative genomic hybridization for prenatal diagnosis:a cohort study of 3171 pregnancies. BJOG 2012; 119(5):614–25.
  • 32. Johnson G, Bachman R. A 46,XY,del(18)(pter-p1100:) cebocephalic child from a 46,XX,t(12;18)(18pter-18p1100::12qter-12pter) normal parent. Hum Genet 1976;34(1):103-6.
  • 33. Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 2000;25(2):205-8.
  • 34. Database of genomic variation, “A curated catalogue of human genomic structural variation”, 2018/09/21, Available from: http://dgv.tcag.ca/dgv/app/variant?id= dgv3407n100&ref=GRCh37/hg19
  • 35. DECIPHER, “Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources”, 2018/09/21 Available from: https://decipher.sanger.ac.uk/patient/291627#genotype/cnv/67391/browser/18:76996166-77946488
  • 36. Varon R, Gooding R, Steglich C, Marns L, Tang H, Angelicheva D et al. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet 2003;35(2):185-9.
  • 37. Choi JS, Lee WJ, Baik SH, Yoon HK, Lee KH, Kim YH. Array CGH reveals genomic aberrations in human emphysema. Lung 2009;187(3):165-72.
There are 37 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section RESEARCH
Authors

Güven Toksoy This is me

Birsen Karaman This is me

Zehra Oya Uyguner This is me

Kader Yılmaz This is me

Recep Has This is me

Hülya Kayserili This is me

Peter Mıny This is me

Seher Başaran This is me

Publication Date March 28, 2019
Submission Date April 9, 2018
Published in Issue Year 2019 Volume: 82 Issue: 1

Cite

APA Toksoy, G., Karaman, B., Uyguner, Z. O., Yılmaz, K., et al. (2019). APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE. Journal of Istanbul Faculty of Medicine, 82(1), 5-11.
AMA Toksoy G, Karaman B, Uyguner ZO, Yılmaz K, Has R, Kayserili H, Mıny P, Başaran S. APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE. İst Tıp Fak Derg. March 2019;82(1):5-11.
Chicago Toksoy, Güven, Birsen Karaman, Zehra Oya Uyguner, Kader Yılmaz, Recep Has, Hülya Kayserili, Peter Mıny, and Seher Başaran. “APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE”. Journal of Istanbul Faculty of Medicine 82, no. 1 (March 2019): 5-11.
EndNote Toksoy G, Karaman B, Uyguner ZO, Yılmaz K, Has R, Kayserili H, Mıny P, Başaran S (March 1, 2019) APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE. Journal of Istanbul Faculty of Medicine 82 1 5–11.
IEEE G. Toksoy, B. Karaman, Z. O. Uyguner, K. Yılmaz, R. Has, H. Kayserili, P. Mıny, and S. Başaran, “APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE”, İst Tıp Fak Derg, vol. 82, no. 1, pp. 5–11, 2019.
ISNAD Toksoy, Güven et al. “APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE”. Journal of Istanbul Faculty of Medicine 82/1 (March 2019), 5-11.
JAMA Toksoy G, Karaman B, Uyguner ZO, Yılmaz K, Has R, Kayserili H, Mıny P, Başaran S. APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE. İst Tıp Fak Derg. 2019;82:5–11.
MLA Toksoy, Güven et al. “APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE”. Journal of Istanbul Faculty of Medicine, vol. 82, no. 1, 2019, pp. 5-11.
Vancouver Toksoy G, Karaman B, Uyguner ZO, Yılmaz K, Has R, Kayserili H, Mıny P, Başaran S. APPLICATION OF MLPA (MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION) IN FETUSES WITH AN ABNORMAL SONOGRAM AND NORMAL KARYOTYPE. İst Tıp Fak Derg. 2019;82(1):5-11.
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