American Journal of Public Health Research
ISSN (Print): 2327-669X ISSN (Online): 2327-6703 Website: http://www.sciepub.com/journal/ajphr Editor-in-chief: Apply for this position
Open Access
Journal Browser
Go
American Journal of Public Health Research. 2013, 1(4), 86-92
DOI: 10.12691/ajphr-1-4-2
Open AccessArticle

Identifying Microdeletion Syndromes in Patients with Intellectual Disability Using Molecular Genetic Testing: An Example for the Brazilian Public Health Care System

Adriana Rosolio Costa Sabbag1, Bruno Garcia Rocha1, Lucimar Retto da Silva de Avó2, Carla Maria Ramos Germano1, 2, Euclides Matheucci Junior1 and Débora Gusmão Melo1, 2,

1Postgraduate Program in Biotechnology, Federal University of São Carlos (UFSCar), São Carlos, SP, Brazil

2Department of Medicine, UFSCar, São Carlos, SP, Brazil

Pub. Date: May 18, 2013

Cite this paper:
Adriana Rosolio Costa Sabbag, Bruno Garcia Rocha, Lucimar Retto da Silva de Avó, Carla Maria Ramos Germano, Euclides Matheucci Junior and Débora Gusmão Melo. Identifying Microdeletion Syndromes in Patients with Intellectual Disability Using Molecular Genetic Testing: An Example for the Brazilian Public Health Care System. American Journal of Public Health Research. 2013; 1(4):86-92. doi: 10.12691/ajphr-1-4-2

Abstract

Unexplained intellectual disability is a clinical situation in which molecular diagnostic techniques should be indicated. The diagnostic yield of Multiplex Ligation-dependent Probe Amplification (MLPA) in a cohort of patients with intellectual disability and dysmorphic features was investigated to identify microdeletion syndromes. We aimed to provide an example of the utilization of MLPA method in the medical care routine that can be useful for planning the inclusion of molecular genetic testing in the Brazilian public health care system. This study was based on 57 patients who had different degrees of intellectual disability with etiology not determined. All patients had normal brain CT scan or MRI and normal karyotype, and patients with environmental damage history were not included. Two of the 57 patients were referred to molecular genetic testing as they were clinically diagnosed as having Williams syndrome. MLPA test costs were calculated (human resources and equipment costs were not included in the calculation). MLPA revealed chromosomal imbalance in 4 out of 57 patients (7%). These imbalances were associated with well-described microdeletion syndromes: 3 patients had Williams syndrome (1 without clinical diagnosis) and 1 patient had 22q11.21 deletion syndrome. The MLPA analysis cost per individual, considering DNA extraction and laboratory reagents, was US$66.40. In this study, MLPA confirmed its value as a promising technique as it has adequate feasible characteristics to identify microdeletion syndromes in patients who had unexplained intellectual disability. This work suggests that MLPA can be a viable alternative to implement molecular genetic testing in the Brazilian public health care system, considering its cost-effectiveness.

Keywords:
biomedical technology assessment molecular diagnostic techniques genetic testing genetic services intellectual disability public health brazil

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Figures

Figure of 1

References:

[1]  GeneTests Medical Genetics Information Resource [Online]. Copyright, University of Washington, Seattle. 1993-2013.
 
[2]  Miller, D.T., Adam, M.P., Aradhya, S., 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, 86(5), 749-764, May 2010.
 
[3]  Mefford, H.C., Batshaw, M.L. and Hoffman, E.P., “Genomics, intellectual disability, and autism”, N Engl J Med, 366(8), 733-743, Feb. 2012.
 
[4]  American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders-DSM-IV-TR. Washington, DC, American Psychiatric Association, 2000, 41-46.
 
[5]  Shevell, M., Ashwal, S., Donley, D., et al. Quality Standards Subcommittee of the American Academy of Neurology and Practice Committee of the Child Neurology Society, “Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society”, Neurology, 60(3), 367-380, Feb. 2003.
 
[6]  Stegmann, A.P., Jonker, L.M. and Engelen, J.J., “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, 51(2), 93-105, Mar-Apr. 2008.
 
[7]  Hochstenbach, R., van Binsbergen, E., Engelen, J., et al. “Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic develop.mental delay in the Netherlands”, Eur J Med Genet, 52(4), 161-169, Jul-Aug. 2009.
 
[8]  Vissers, L.E., de Vries, B.B. and Veltman, J.A. “Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis”, J Med Genet, 47(5), 289-297, May 2010.
 
[9]  Moeschler, J.B., “Genetic evaluation of intellectual disabilities”, Semin Pediatr Neurol, 15(1), 2-9, Mar. 2008.
 
[10]  Galasso, C., Lo-Castro, A., El-Malhany, N. and Curatolo, P. “Idiopathic mental retardation and new chromosomal abnormalities”, Ital J Pediatr, 36, 17, Feb. 2010.
 
[11]  Rauch, A., Hoyer, J., Guth, S., et al. “Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation”, Am J Med Genet A, 140(19), 2063-2074, Oct. 2006.
 
[12]  Bernardini, L., Alesi, V., Loddo, S., et al. “High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?” Eur J Hum Genet, 18(2), 178-185, Feb. 2010.
 
[13]  Makela, N.L., Birch, P.H., Friedman, J.M. and Marra, C.A., “Parental perceived value of a diagnosis for intellectual disability (ID): a qualitative comparison of families with and without a diagnosis for their child's ID”, Am J Med Genet A, 149A (11), 2393-2402, Nov. 2009.
 
[14]  Lewis, C., Skirton, H. and Jones, R. “Living without a diagnosis: the parental experience”, Genet Test Mol Biomarkers, 14(6), 807-815, Dec. 2010.
 
[15]  Madeo, A.C., O'Brien, K.E., Bernhardt, B.A. and Biesecker, B.B., “Factors associated with perceived uncertainty among parents of children with undiagnosed medical conditions”, Am J Med Genet A, 158A (8), 1877-1884, Aug. 2012.
 
[16]  Cassidy, S.B. and Allanson, J. (eds.), Management of Genetic Syndromes, 2nd ed. Hoboken, NJ, John Wiley & Sons, 2005.
 
[17]  Van Karnebeek, C.D., Jansweijer, M.C., Leenders, A.G., Offringa, M. and Hennekam, R.C., “Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness”, Eur J Hum Genet, 13(1), 6-25, Jan. 2005.
 
[18]  Hastings, R.J., Cavani, S., Bricarelli, F.D., Patsalis, P.C., Kristoffersson, U. and ECA PWG Co-ordinators, “Cytogenetic Guidelines and Quality Assurance: a common European framework for quality assessment for constitutional and acquired cytogenetic investigations”, Eur J Hum Genet, 15(5), 525-527, May. 2007.
 
[19]  Vissers, L.E. and Stankiewicz, P., “Microdeletion and microduplication syndromes”, Methods Mol Biol, 838, 29-75, 2012.
 
[20]  Shaffer, L.G., Bejjani, B.A., Torchia, B., Kirkpatrick, S., Coppinger, J. and Ballif, B.C., “The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future”, Am J Med Genet C Semin Med Genet, 145C (4), 335-345, Nov. 2007.
 
[21]  Li, M.M. and Andersson, H.C., “Clinical application of microarray-based molecular cytogenetics: an emerging new era of genomic medicine”, J Pediatr, 155(3), 311-317, 2009.
 
[22]  Kirchhoff, M., Bisgaard, A.M., Bryndorf, T. and 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, 50(1), 33-42, Jan-Feb. 2007.
 
[23]  Jehee, F.S., Takamori, J.T., Medeiros, P.F., Pordeus, A.C., Latini, F.R., Bertola, D.R., Kim, C.A. and Passos-Bueno, M.R., “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, 54(4), e425-432, Jul-Aug. 2011.
 
[24]  Schouten, J.P., McElgunn, C.J., Waaijer, R., et al. “Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification”, Nucleic Acids Res, 30(12), e57, Jun. 2002.
 
[25]  Shaw-Smith, C., Redon, R., Rickman, L., et al. “Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features”, J Med Genet, 41(4), 241-248, Apr. 2004.
 
[26]  Krepischi-Santos, A.C., Vianna-Morgante, A.M., Jehee, F.S., et al. “Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations”, Cytogenet Genome Res, 115(3-4), 254-261, 2006.
 
[27]  Bruno, D.L., Ganesamoorthy, D., Schoumans, J., et al. “Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice”, J Med Genet, 46(2), 123-131, Feb. 2009.
 
[28]  Gijsbers, A.C., Lew, J.Y., Bosch, C.A., et al. “A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first”, Eur J Hum Genet, 17(11), 1394-1402, Nov. 2009.
 
[29]  Regier, D.A., Friedman, J.M. and Marra, C.A., “Value for money? Array genomic hybridization for diagnostic testing for genetic causes of intellectual disability”, Am J Hum Genet, 86(5), 765-772, May 2010.
 
[30]  Slavotinek, A.M. “Novel microdeletion syndromes detected by chromosome microarrays”, Hum Genet, 124(1), 1-17, Aug. 2008.
 
[31]  Vieira, T.P., Sgardioli, I.C. and Gil-da-Silva-Lopes, V.L. “Genetics and public health: the experience of a reference center for diagnosis of 22q11.2 deletion in Brazil and suggestions for implementing genetic testing”, J Community Genet, 4(1), 99-106, Jan. 2012.
 
[32]  Programa das Nações Unidas para o Desenvolvimento do Brasil (PNUD Brasil). “Atlas do Desenvolvimento Humano no Brasil”, 2002. [Accessed April 16, 2013].
 
[33]  Pober, B.R., “Williams-Beuren syndrome”, N Engl J Med, 362(3), 239-252, Jan. 2010.
 
[34]  McDonald-McGinn, D.M. and Sullivan, K.E., “Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome)”, Medicine (Baltimore), 90(1), 1-18, Jan. 2011.
 
[35]  Paim, J., Travassos, C., Almeida, C., Bahia, L. and Macinko, J. “The Brazilian health system: history, advances, and challenges”, Lancet, 377(9779), 1778-1797, May 2011.
 
[36]  Horovitz, D.D., Cardoso, M.H., Llerena, J.C. Jr., de Mattos, R.A., “Birth defects in Brazil and health care: proposals for public policies in clinical genetics”, Cad Saude Publica 22(12): 2599-2609, Dec. 2006.
 
[37]  Castilla, E.E. and Luquetti, D.V., “Brazil: public health genomics”, Public Health Genomics, 12(1), 53-58, 2009.
 
[38]  Horovitz, D.D., de Faria Ferraz, V.E., Dain, S. and Marques-de-Faria, A.P. “Genetic services and testing in Brazil”, J Community Genet, [Epub ahead of print], May 2012.
 
[39]  Melo, D.G. and Sequeiros, J., “The challenges of incorporating genetic testing in the unified national health system in Brazil”, Genet Test Mol Biomarkers, 16(7), 651-655, Jul. 2012.
 
[40]  Brasil, Ministério da Saúde, Gabinete do Ministro. “Portaria No 81, de 20 de janeiro de 2009 - Institui, no âmbito do SUS, a Política Nacional de Atenção Integral em Genética Clínica”, Diário Oficial da União da República Federativa do Brasil, Brasília, 21 de janeiro de 2009. [Accessed April 16, 2013].
 
[41]  Scheffer, M., Biancarelli, A., Cassenote, A. (coords.), “Demografia Médica no Brasil: dados gerais e descrições de desigualdades”, São Paulo: Conselho Regional de Medicina do Estado de São Paulo e Conselho Federal de Medicina, 2011. [Accessed April 16, 2013].