Yonsei Med J.  2013 Nov;54(6):1463-1470. 10.3349/ymj.2013.54.6.1463.

Array-Based Comparative Genomic Hybridization in 190 Korean Patients with Developmental Delay and/or Intellectual Disability: A Single Tertiary Care University Center Study

• Lee CG
• Park SJ
• Yun JN
• Ko JM
• Kim HJ
• Yim SY
• Sohn YB

• KMID: 1798144
• DOI: http://doi.org/10.3349/ymj.2013.54.6.1463

Abstract

PURPOSE
This study analyzed and evaluated the demographic, clinical, and cytogenetic data [G-banded karyotyping and array-based comparative genomic hybridization (array CGH)] of patients with unexplained developmental delay or intellectual disability at a single Korean institution.
MATERIALS AND METHODS
We collected clinical and cytogenetic data based on retrospective charts at Ajou University Medical Center, Suwon, Korea from April 2008 to March 2012.
RESULTS
A total of 190 patients were identified. Mean age was 5.1+/-1.87 years. Array CGH yielded abnormal results in 26 of 190 patients (13.7%). Copy number losses were about two-fold more frequent than gains. A total of 61.5% of all patients had copy number losses. The most common deletion disorders included 22q11.2 deletion syndrome, 15q11.2q12 deletion and 18q deletion syndrome. Copy number gains were identified in 34.6% of patients, and common diseases among these included Potocki-Lupski syndrome, 15q11-13 duplication syndrome and duplication 22q. Abnormal karyotype with normal array CGH results was exhibited in 2.6% of patients; theses included balanced translocation (n=2), inversion (n=2) and low-level mosaicism (n=1). Facial abnormalities (p<0.001) and failure to thrive were (p<0.001) also more frequent in the group of patients with abnormal CGH findings.
CONCLUSION
Array CGH is a useful diagnostic tool in clinical settings in patients with developmental delay or intellectual disability combined with facial abnormalities or failure to thrive.

Keyword

Array CGH; copy number variations; developmental delay; intellectual disability

MeSH Terms

Adolescent
Adult
Child
Child, Preschool
Comparative Genomic Hybridization/*methods
Female
Gene Dosage/genetics
Humans
Infant
Intellectual Disability/*genetics
Karyotype
Male
Republic of Korea
Retrospective Studies
Tertiary Healthcare/statistics & numerical data
Young Adult

Reference

1. Jeevanandam L. Perspectives of intellectual disability in Asia: epidemiology, policy, and services for children and adults. Curr Opin Psychiatry. 2009; 22:462–468.

2. Kwok HW, Chui EM. A survey on mental health care for adults with intellectual disabilities in Asia. J Intellect Disabil Res. 2008; 52:996–1002.

3. Croen LA, Grether JK, Selvin S. The epidemiology of mental retardation of unknown cause. Pediatrics. 2001; 107:E86.

4. Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, Becker C, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A. 2006; 140:2063–2074.

5. Shaffer LG, Bejjani BA. Medical applications of array CGH and the transformation of clinical cytogenetics. Cytogenet Genome Res. 2006; 115:303–309.

6. Oostlander AE, Meijer GA, Ylstra B. Microarray-based comparative genomic hybridization and its applications in human genetics. Clin Genet. 2004; 66:488–495.

7. Lee C, Iafrate AJ, Brothman AR. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet. 2007; 39:7 Suppl. S48–S54.

8. 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; 86:749–764.

9. Stankiewicz P, Beaudet AL. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. 2007; 17:182–192.

10. D'Amours G, Kibar Z, Mathonnet G, Fetni R, Tihy F, Désilets V, et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet. 2012; 81:128–141.

11. Shoukier M, Klein N, Auber B, Wickert J, Schröder J, Zoll B, et al. Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants? Clin Genet. 2013; 83:53–65.

12. Klinger G, Merlob P. Elements of morphology: standard terminology for the ear--additional features. Am J Med Genet A. 2009; 149A:1606.

13. Merks JH, van Karnebeek CD, Caron HN, Hennekam RC. Phenotypic abnormalities: terminology and classification. Am J Med Genet A. 2003; 123A:211–230.

14. Shaffer LG, Bejjani BA, Torchia B, Kirkpatrick S, Coppinger J, Ballif BC. The identification of microdeletion syndromes and otherchromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet C Semin Med Genet. 2007; 145C:335–345.

15. Dale RC, Grattan-Smith P, Nicholson M, Peters GB. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol. 2012; 54:618–623.

16. Kurian MA. The clinical utility of chromosomal microarray in childhood neurological disorders. Dev Med Child Neurol. 2012; 54:582–583.

17. Wincent J, Anderlid BM, Lagerberg M, Nordenskjöld M, Schoumans J. High-resolution molecular karyotyping in patients with developmental delay and/or multiple congenital anomalies in a clinical setting. Clin Genet. 2011; 79:147–157.

18. Park SJ, Jung EH, Ryu RS, Kang HW, Ko JM, Kim HJ, et al. Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases. Mol Cytogenet. 2011; 4:12.

19. Shen Y, Irons M, Miller DT, Cheung SW, Lip V, Sheng X, et al. Development of a focused oligonucleotide-array comparative genomic hybridization chip for clinical diagnosis of genomic imbalance. Clin Chem. 2007; 53:2051–2059.

20. Zahir F, Friedman JM. The impact of array genomic hybridization on mental retardation research: a review of current technologies and their clinical utility. Clin Genet. 2007; 72:271–287.

21. Horev G, Ellegood J, Lerch JP, Son YE, Muthuswamy L, Vogel H, et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc Natl Acad Sci U S A. 2011; 108:17076–17081.

22. Shchelochkov OA, Cheung SW, Lupski JR. Genomic and clinical characteristics of microduplications in chromosome 17. Am J Med Genet A. 2010; 152A:1101–1110.

23. Ballif BC, Hornor SA, Sulpizio SG, Lloyd RM, Minier SL, Rorem EA, et al. Development of a high-density pericentromeric region BAC clone set for the detection and characterization of small supernumerary marker chromosomes by array CGH. Genet Med. 2007; 9:150–162.

24. Huang C, Yang YF, Yin N, Chen JL, Wang J, Zhang H, et al. Congenital heart defect and mental retardation in a patient with a 13q33.1-34 deletion. Gene. 2012; 498:308–310.

25. Frye RE. Mitochondrial disease in 22q13 duplication syndrome. J Child Neurol. 2012; 27:942–949.

26. Peeters H, Vermeesch J, Fryns JP. A cryptic duplication 22q13.31 to qter leads to a distinct phenotype with mental retardation, microcephaly and mild facial dysmorphism. Genet Couns. 2008; 19:365–371.

27. Machado IN, Heinrich JK, Campanhol C, Rodrigues-Peres RM, Oliveira FM, Barini R. Prenatal diagnosis of a partial trisomy 13q (q14-->qter): phenotype, cytogenetics and molecular characterization by spectral karyotyping and array comparative genomic hybridization. Genet Mol Res. 2010; 9:441–448.

28. Shinawi M, Shao L, Jeng LJ, Shaw CA, Patel A, Bacino C, et al. Low-level mosaicism of trisomy 14: phenotypic and molecular characterization. Am J Med Genet A. 2008; 146A:1395–1405.

29. von Sneidern E, Lacassie Y. Is trisomy 14 mosaic a clinically recognizable syndrome?--case report and review. Am J Med Genet A. 2008; 146A:1609–1613.