Display options
Cite
Cai G, Edelmann L, Goldsmith JE, et al. Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC Med Genomics. 2008;1:50doi: 10.1186/1755-8794-1-50.
Cai, G., Edelmann, L., Goldsmith, J. E., Cohen, N., Nakamine, A., Reichert, J. G., Hoffman, E. J., Zurawiecki, D. M., Silverman, J. M., Hollander, E., Soorya, L., Anagnostou, E., Betancur, C., & Buxbaum, J. D. (2008). Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC medical genomics, 150. https://doi.org/10.1186/1755-8794-1-50
Cai, Guiqing, et al. "Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT." BMC medical genomics vol. 1 (2008): 50. doi: https://doi.org/10.1186/1755-8794-1-50
Cai G, Edelmann L, Goldsmith JE, Cohen N, Nakamine A, Reichert JG, Hoffman EJ, Zurawiecki DM, Silverman JM, Hollander E, Soorya L, Anagnostou E, Betancur C, Buxbaum JD. Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC Med Genomics. 2008 Oct 16;1:50. doi: 10.1186/1755-8794-1-50. PMID: 18925931; PMCID: PMC2588447.
Copy Download .nbib Format: NLM
Share it on

BMC Med Genomics. 2008 Oct 16;1:50. doi: 10.1186/1755-8794-1-50.

Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT.

BMC medical genomics

Guiqing Cai, Lisa Edelmann, Juliet E Goldsmith, Ninette Cohen, Alisa Nakamine, Jennifer G Reichert, Ellen J Hoffman, Danielle M Zurawiecki, Jeremy M Silverman, Eric Hollander, Latha Soorya, Evdokia Anagnostou, Catalina Betancur, Joseph D Buxbaum

Affiliations

  1. Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. [email protected]

PMID: 18925931 PMCID: PMC2588447 DOI: 10.1186/1755-8794-1-50

Abstract

BACKGROUND: It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.

METHODS: In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.

RESULTS: MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6-7% of the cases but in only 2% of controls (P = 0.003).

CONCLUSION: MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.

References

  1. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8 - PubMed
  2. Am J Hum Genet. 2008 Jan;82(1):199-207 - PubMed
  3. Annu Rev Genomics Hum Genet. 2004;5:379-405 - PubMed
  4. Genet Couns. 2003;14(3):267-79 - PubMed
  5. Science. 2007 Apr 20;316(5823):445-9 - PubMed
  6. Ann Med. 2003;35(4):274-81 - PubMed
  7. Autism. 2004 Jun;8(2):141-61 - PubMed
  8. Mol Psychiatry. 2002;7(3):311-6 - PubMed
  9. J Cell Biol. 1999 Jul 26;146(2):477-92 - PubMed
  10. Nat Genet. 1997 Nov;17(3):357-61 - PubMed
  11. Am J Hum Genet. 2003 Mar;72(3):539-48 - PubMed
  12. JAMA. 2007 Mar 7;297(9):940 - PubMed
  13. Mol Psychiatry. 2007 Nov;12(11):977-9 - PubMed
  14. Am J Med Genet. 2002 Mar 8;114(2):137-43 - PubMed
  15. Hum Genet. 2006 Aug;120(1):93-100 - PubMed
  16. Nat Genet. 2007 Mar;39(3):319-28 - PubMed
  17. Am J Hum Genet. 2007 Apr;80(4):633-49 - PubMed
  18. BMC Med Genet. 2005 Jan 18;6:3 - PubMed
  19. Am J Hum Genet. 2008 Feb;82(2):477-88 - PubMed
  20. Eur Child Adolesc Psychiatry. 2007 Aug;16(5):305-8 - PubMed
  21. Am J Hum Genet. 2005 May;76(5):865-76 - PubMed
  22. Eur J Hum Genet. 2007 Jun;15(6):658-63 - PubMed
  23. J Autism Dev Disord. 1997 Oct;27(5):501-17 - PubMed
  24. J Autism Dev Disord. 2005 Aug;35(4):461-70 - PubMed
  25. Genet Med. 2006 Sep;8(9):549-56 - PubMed
  26. Am J Med Genet A. 2004 Feb 1;124A(4):413-5 - PubMed
  27. Mol Psychiatry. 2008 Jan;13(1):90-8 - PubMed
  28. Genet Med. 2001 Jan-Feb;3(1):79-84 - PubMed
  29. Am J Med Genet. 2000 Feb 7;96(1):43-8 - PubMed
  30. Curr Psychiatry Rep. 2007 Apr;9(2):148-58 - PubMed
  31. Am J Hum Genet. 2003 Nov;73(5):1027-40 - PubMed
  32. Am J Hum Genet. 1997 Apr;60(4):928-34 - PubMed
  33. J Autism Dev Disord. 2008 Oct;38(9):1634-41 - PubMed
  34. Eur J Med Genet. 2007 Jan-Feb;50(1):33-42 - PubMed
  35. J Autism Dev Disord. 1994 Oct;24(5):659-85 - PubMed
  36. Hum Mol Genet. 1999 Dec;8(13):2497-505 - PubMed
  37. J Med Genet. 2007 Jul;44(7):452-8 - PubMed
  38. J Med Genet. 2007 Feb;44(2):136-43 - PubMed
  39. J Autism Dev Disord. 2007 Apr;37(4):694-702 - PubMed
  40. Hum Genet. 1999 Jan;104(1):43-8 - PubMed
  41. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):615-22 - PubMed
  42. J Med Genet. 2006 Nov;43(11):843-9 - PubMed
  43. Dev Psychopathol. 2005 Summer;17(3):753-84 - PubMed
  44. Am J Hum Genet. 1998 May;62(5):1077-83 - PubMed
  45. Eur J Hum Genet. 2006 Aug;14(8):923-31 - PubMed
  46. Hum Mol Genet. 2006 Mar 15;15(6):853-69 - PubMed
  47. Eur J Hum Genet. 2002 Jan;10(1):26-35 - PubMed
  48. Neurosci Lett. 2007 Jun 21;421(1):57-61 - PubMed
  49. Clin Genet. 2002 Jul;62(1):89-93 - PubMed
  50. Hum Mol Genet. 2007 Mar 15;16(6):691-703 - PubMed
  51. J Neurosci. 2006 May 17;26(20):5383-92 - PubMed
  52. Nat Genet. 2007 Oct;39(10):1266-72 - PubMed
  53. J Med Genet. 2008 Apr;45(4):239-43 - PubMed
  54. Nat Genet. 2000 Feb;24(2):167-70 - PubMed
  55. Brain Dev. 2007 Jun;29(5):257-72 - PubMed
  56. Genet Med. 2007 Jul;9(7):427-41 - PubMed
  57. Mol Psychiatry. 2006 Jan;11(1):1, 18-28 - PubMed
  58. Hum Mol Genet. 2007 Nov 15;16(22):2713-9 - PubMed
  59. JAMA. 2003 Jan 1;289(1):49-55 - PubMed
  60. Hum Mutat. 2007 Oct;28(10):1034-42 - PubMed
  61. Hum Mol Genet. 2008 Feb 15;17(4):628-38 - PubMed
  62. J Med Genet. 2002 Jun;39(6):430-3 - PubMed
  63. Genome Biol. 2007;8(2):R19 - PubMed
  64. N Engl J Med. 2008 Feb 14;358(7):667-75 - PubMed
  65. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13 - PubMed
  66. Am J Med Genet. 2002 Nov 1;112(4):400-4 - PubMed
  67. Hum Mutat. 2004 May;23(5):413-9 - PubMed
  68. Brain Dev. 2005 Aug;27(5):365-9 - PubMed
  69. Am J Med Genet A. 2008 Mar 1;146A(5):636-43 - PubMed
  70. Hum Mol Genet. 1999 May;8(5):783-93 - PubMed
  71. Hum Mol Genet. 1999 Jul;8(7):1157-67 - PubMed

Publication Types

Grant support