• NEETHA JOHN Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
  • SHARMA PSVN Department of Psychiatry, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.
  • RAJASEKHAR MOKA Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.


Objective: Intellectual disability is the most common developmental disorder that originates before the age of 18 years and is characterized by limitation in intellectual functioning and adaptive behaviour. The fact that >30 to 50% of all causes are still unknown in etiology is increasing the burden of the clinical evaluators and managers handling these children. The purpose of this study was to have an optimal genetic diagnostic evaluation to assist paediatricians in providing medical advice for children with intellectual disabilities and global developmental delays.

Methods: The study was initiated with 385 cases; however, only 201 cases had no cytogenetic abnormality and negative for PCR test for FXS. However, these subjects showed characteristic signs of facial dysmorphisms, developmental delay, mild to severe intellectual disability, which were unique and unspecific with lack of major hallmarks for any particular syndrome/phenotype, considered as “idiopathic” and tested for MLPA analysis and subsequently confirmed by FISH and RT-qPCR.

Results: A total of 23 (11.44%) cases were found to have submicroscopic chromosomal variations [microdeletions (18 cases), microduplications (5 cases)]. We categorized the aberrations detected in these cases as novel and as variants of uncertain significance. All these cases showed clear evidence for segregation of the variation and were provided with the required genetic counselling.

Conclusion: MLPA method gives a better yield in combination with karyotype analysis. The detection rate as per current analysis suggests that the use of MLPA could be a robust, high throughput yet cost-effective technique for use in a diagnostic set up.

Keywords: Intellectual disabilities, Global developmental delay, Chromosomal variations, Copy number variations


1. Curry CJ, Stevenson RE, Aughton D, Byrne J, Carey JC, Cassidy S, et al. Evaluation of mental retardation: recommendations of a consensus conference: American College of Medical Genetics. Am J Med Genet 1997;72:468-77.
2. Karam SM, Riegel M, Segal SL, Félix TM, Barros AJ, Santos IS, et al. Genetic causes of intellectual disability in a birth cohort: A population-based study. Am J Med Genet A 2015;167:1204-14.
3. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: An exome sequencing study. Lancet 2012;380:1674-82.
4. Moeschler JB. Genetic evaluation of intellectual disabilities. Semin Pediatr Neurol 2008;15:2.
5. Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: A review. J Neurodev Disord 2010;2:182-209.
6. 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;30:e57.
7. Moorhead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res 1960;20:613-6.
8. de Vries BB, White SM, Knight SJ, Regan R, Homfray T, Young ID, et al. Clinical studies on submicroscopic subtelomeric rearrangements: A checklist. J Med Genet 2001;38:145-50.
9. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. Working Group of the American College of Medical Genetics Laboratory Quality, Assurance Committee. American college of medical genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011;13:680-5.
10. Leung IY, Pooh RK, Wang CC, Lau TK, Choy KW. Classification of pathogenic or benign status of CNVs detected by microarray analysis. Expert Rev Mol Diagn 2010;10:717-21.
11. John N, Rajasekhar M, Girisha KM, Sharma PS, Gopinath PM. Multiplex ligation-dependant probe amplification study of children with idiopathic mental retardation in South India. Indian J Hum Genet 2013;19:165-70.
12. Boggula VR, Shukla A, Danda S, Hariharan SV, Nampoothiri S, Kumar R, et al. Clinical utility of multiplex ligation-dependent probe amplification technique in identification of aetiology of unexplained mental retardation: A study in 203 Indian patients. Indian J Med Res 2014;139:66-75.
13. Zwanenburg RJ, Ruiter SA, van den Heuvel ER, Flapper BC, Van Ravenswaaij-Arts CM. Developmental phenotype in Phelan-McDermid (22q13.3 deletion) syndrome: A systematic and prospective study in 34 children. J Neurodev Disord 2016;8:16.
14. Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 2010;42:489-91.
15. Chen J, Yu S, Fu Y, Li X. Synaptic proteins and receptors defects in autism spectrum disorders. Front Cell Neurosci 2014;8:276.
16. Rafati M, Seyyedaboutorabi E, Ghadirzadeh MR, Heshmati Y, Adibi H, Keihanidoust Z, et al. “Familial” versus “Sporadic” intellectual disability: Contribution of common microdeletion and microduplication syndromes. Mol Cytogenet 2012;5:9.
17. Todorovski Z, Asrar S, Liu J, Saw NM, Joshi K, Cortez MA, et al. LIMK1 regulates long-term memory and synaptic plasticity via the transcriptional factor CREB. Mol Cell Biol 2015;35:1316-28.
18. Magoulas PL, El-Hattab AW. Chromosome 15q24 microdeletion syndrome. Orphanet J Rare Dis 2012;7:2.
19. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med 2012;366:733-43.
20. Willatt L, Cox J, Barber J, Cabanas ED, Collins A, Donnai D, et al. 3q29 microdeletion syndrome: Clinical and molecular characterization of a new syndrome. Am J Hum Genet 2005;77:154-60.
21. Sagar A, Bishop JR, Tessman DC, Guter S, Martin CL, Cook EH. Co-occurrence of autism, childhood psychosis, and intellectual disability associated with a de novo 3q29 microdeletion. Am J Med Genet A 2013;161A:845-9.
22. Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, et al. Quaternary structure, protein dynamics and synaptic function of SAP97 controlled by L27 domain interaction. Neuron 2004;44:453-67.
23. Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, Habel A, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011;159:332-90.
24. Pollak DD, Herkner K, Hoeger H, Lubec G. Behavioral testing upregulates pCaMKII, BDNF, PSD-95 and egr-1 in hippocampus of FVB/N mice. Behav Brain Res 2005;163:128-35.
25. McDonald-McGinn DM, Fahiminiya S, Revil T, Nowakowska BA, Suhl J, Bailey A, et al. Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J Med Genet 2013;50:80-90.
26. Friedman J, Adam S, Arbour L, Armstrong L, Baross A, Birch P, et al. Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization. BMC Genomics 2009;10:526.
27. Scala E, Longo I, Ottimo F, Speciale C, Sampieri K, Katzaki E, et al. MECP2 deletions and genotype-phenotype correlation in Rett syndrome. Am J Med Genet A 2007;143A:2775-84.
28. Na ES, Nelson ED, Kavalali ET, Monteggia LM. The impact of MeCP2 loss- or gain-of-function on synaptic plasticity. Neuropsychopharmacology 2013;38:212-9.
29. Stockler-Ipsiroglu S, van Karnebeek CD. Cerebral creatine deficiencies: A group of treatable intellectual developmental disorders. Semin Neurol 2014;34:350-6.
30. Cervera-Acedo C, Lopez M, Aguirre-Lamban J, Santibañez P, Garcia-Oguiza A, Poch-Olive ML, et al. A novel SLC6A8 mutation associated with motor dysfunction in a child exhibiting creatine transporter deficiency. Hum Genome Var 2015;2:15037.
31. Rooms L, Reyniers E, van Luijk R, Scheers S, Wauters J, Ceulemans B, et al. Subtelomeric deletions detected in patients with idiopathic mental retardation using multiplex ligation-dependent probe amplification (MLPA). Hum Mutat 2004;23:17-21.
32. Sogaard M, Tümer Z, Hjalgrim H, Hahnemann J, Friis B, Ledaal P, et al. Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter. BMC Med Genet 2005;6:21.
33. Erjavec-Skerget A, Stangler-Herodez S, Zagorac A, Zagradisnik B, Kokalj-Vokac N. Subtelomeric chromosome rearrangements in children with idiopathic mental retardation: Applicability of three molecular-cytogenetic methods. Croat Med J 2006;47:841-50.
34. Wang S, Pan H, Pei P, Zheng X, Zhang Y, Ma Y, et al. Multiplex ligation-dependent probe amplification for detecting submicroscopic chromosomal abnormalities in Chinese children with global developmental delay or intellectual disability. Zhonghua Yi Xue Za Zhi 2014;94:2514-8.
85 Views | 116 Downloads
How to Cite
JOHN, N., S. PSVN, and R. MOKA. “SUBMICROSCOPIC CHROMOSOMAL VARIATIONS IN CHILDREN WITH IDIOPATHIC INTELLECTUAL AND DEVELOPMENTAL DISABILITIES”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 13, no. 2, Feb. 2020, pp. 188-91, doi:10.22159/ajpcr.2020.v13i2.36405.
Original Article(s)