Detection of chromosomal imbalances using combined MLPA kits in patients with syndromic intellectual disability

Open access

Abstract

Intellectual disability (ID) is a common disorder, with major consequences for individual, family and society. Due to clinical and genetic heterogeneity of ID, in about 50% of cases an etiologic diagnosis cannot be established. The aim of this study was to evaluate the ability of a combination of MLPA kits to establish the diagnosis in 369 patients with syndromic ID and normal or uncertain routine karyotype results. All patients were assessed for chromosome imbalance using SALSA MLPA P064 or P096 kits, if the phenotype was suggestive of a microdeletion syndrome (subgroup A - 186 patients), or subtelomeric P036 and P070 kits, if the phenotype was not suggestive of a microdeletion syndrome or if the result of the standard karyotype was uncertain (subgroup B - 183 patients). Abnormal results detected by these kits were further characterized using appropriate follow-up MLPA kits (Telomere Follow-up set, P029-A1, P250-B2, ME028-B1). In subgroup A we identified 25 patients with microdeletions (13.4%). Using subtelomere screening and follow-up kits in subgroup B we detected cryptic rearrangements in 7.5% cases and identified the origin of the unknown material noticed in the standard karyotype in 10 out of 11 patients. Summarizing data from the two groups, the combined use of MLPA kits led to the diagnosis in 10.6% (38/358) patients with normal karyotype. Using follow-up MLPA kits allowed us both to confirm abnormalities and to determine their size, which facilitated the interpretation of the clinical significance of these rearrangements. For laboratories that do not have yet access to microarray technology, using several MLPA kits represents an effective strategy for establishing the diagnosis in ID patients.

1. Roeleveld N, Zielhuis GA, Gabreels F. The prevalence of mental retardation: a critical review of recent literature.

Dev Med Child Neurol. 1997 Feb;39(2):125-32.

DOI: 10.1111/j.1469-8749.1997.tb07395.x

2. 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. DOI: 10.1016/j.ajhg.2010.04.006

3. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011

Sep;43(9):838-46. DOI: 10.1038/ng.909

4. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002 Jun 15;30(12):e57. DOI: 10.1093/nar/gnf056

5. Slavotinek AM. Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet. 2008

Aug;124(1):1-17. DOI: 10.1007/s00439-008-0513-9

6. Kirchhoff M, Bisgaard AM, Bryndorf T, Gerdes T.

MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions. Eur J Med Genet. 2007 Jan-Feb;50(1):33-42. DOI: 10.1016/j. ejmg.2006.10.002

7. Jehee FS, Takamori JT, Medeiros PF, Pordeus AC, Latini FR, Bertola DR, et al. Using a combination of MLPA kits to detect chromosomal imbalances in patients with multiple congenital anomalies and mental retardation is a valuable choice for developing countries. Eur J Med Genet. 2011 Jul-Aug;54(4):e425-32. DOI: 10.1016/j. ejmg.2011.03.007

Fusco C, Micale L, Augello B, Teresa Pellico M, Menghini D, Alfieri P, et al. Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits. Eur J Hum Genet. 2014 Jan;22(1):64-70. DOI: 10.1038/ejhg.2013.101

9. Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome. Am J Med Genet A. 2008 Apr 1;146(7):854-60. DOI: 10.1002/ajmg.a.32249

10. Northrop EL, Ren H, Bruno DL, McGhie JD, Coffa J, Schouten J, et al. Detection of cryptic subtelomeric chromosome abnormalities and identification of anonymous chromatin using a quantitative multiplex ligation-dependent probe amplification (MLPA) assay.

Hum Mutat. 2005 Nov;26(5):477-86. DOI: 10.1002/ humu.20243

11. Kirchhoff M, Gerdes T, Brunebjerg S, Bryndorf T.

Investigation of patients with mental retardation and dysmorphic features using comparative genomic hybridization and subtelomeric multiplex ligation dependent probe amplification. Am J Med Genet A. 2005 Dec 15;139(3):231-3. DOI: 10.1002/ajmg.a.31019

12. Rooms L, Reyniers E, Wuyts W, Storm K, van Luijk R, Scheers S, et al. Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics. Clin Genet. 2006 Jan;69(1):58-64.

DOI: 10.1111/j.1399-0004.2005.00545.x

13. Biesecker LG. The end of the beginning of chromosome ends. Am J Med Genet. 2002 Feb 1;107(4):263-6.

DOI: 10.1002/ajmg.10160 DOI: 10.1002/ajmg.10160. abs

14. Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN, Hedrick J, Eash D, et al. Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J Med Genet. 2006

Jun;43(6):478-89. DOI: 10.1136/jmg.2005.036350

15. Koolen DA, Nillesen WM, Versteeg MH, Merkx GF, Knoers NV, Kets M, et al. Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet. 2004

Dec;41(12):892-9. DOI: 10.1136/jmg.2004.023671

16. Ahn JW, Ogilvie CM, Welch A, Thomas H, Madula R, Hills A, et al. Detection of subtelomere imbalance using MLPA: validation, development of an analysis protocol, and application in a diagnostic centre. BMC Med Genet. 2007;8:9. DOI: 10.1186/1471-2350-8-9

17. Ahn JW, Mann K, Docherty Z, Mackie Ogilvie C. Submicroscopic chromosome imbalance in patients with developmental delay and/or dysmorphism referred specifically for Fragile X testing and karyotype analysis.

Mol Cytogenet. 2008;1:2. DOI: 10.1186/1755-8166-1-2

18. Stegmann AP, Jonker LM, Engelen JJ. Prospective screening of patients with unexplained mental retardation using subtelomeric MLPA strongly increases the detection rate of cryptic unbalanced chromosomal rearrangements. Eur J Med Genet. 2008 Mar- Apr;51(2):93-105. DOI: 10.1016/j.ejmg.2007.10.003

19. Wu Y, Ji T, Wang J, Xiao J, Wang H, Li J, et al. Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation. BMC Med Genet. 2010;11:72. DOI: 10.1186/1471-2350-11-72

20. Medina A, Pineros L, Arteaga C, Velasco H, Izquierdo A, Giraldo A, et al. Multiplex ligation-dependent probe amplification to subtelomeric rearrangements in idiopathic intellectual disability in Colombia. Pediatr Neurol. 2014 Mar;50(3):250-4. DOI: 10.1016/j.pediatrneurol.

2013.10.017

21. Mundhofir FE, Nillesen WM, Van Bon BW, Smeets D, Pfundt R, van de Ven-Schobers G, et al. Subtelomeric chromosomal rearrangements in a large cohort of unexplained intellectually disabled individuals in Indonesia: A clinical and molecular study. Indian J Hum Genet. 2013 Apr;19(2):171-8. DOI: 10.4103/0971-6866.116118

22. Pohovski LM, Dumic KK, Odak L, Barisic I. Multiplex ligation-dependent probe amplification workflow for the detection of submicroscopic chromosomal abnormalities in patients with developmental delay/intellectual disability. Mol Cytogenet. 2013;6(1):7. DOI: 10.1186/1755-8166-6-7

23. 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. DOI: 10.1016/j. ejmg.2009.03.015

24. Kriek M, Knijnenburg J, White SJ, Rosenberg C, den Dunnen JT, van Ommen GJ, et al. Diagnosis of genetic abnormalities in developmentally delayed patients: a new strategy combining MLPA and array-CGH.

Am J Med Genet A. 2007 Mar 15;143(6):610-4. DOI: 10.1002/ajmg.a.31593

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

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