Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Public Health | Research

Testing criteria for 22q11.2 deletion syndrome: preliminary results of a low cost strategy for public health

Authors: Ilária Cristina Sgardioli, Fabíola Paoli Monteiro, Paulo Fanti, Társis Paiva Vieira, Vera Lúcia Gil-da-Silva-Lopes

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

Login to get access

Abstract

Background

The clinical heterogeneity of the 22q11.2 Deletion Syndrome (22q11.2DS – OMIM, #188400 and #192430) is a universal challenge leading to diagnostic delay. The aim of this study was to evaluate a low cost strategy for the diagnosis of this condition based upon clinical criteria previously reported. Health professionals, who collected clinical data, from twelve centers were trained in those criteria, which were summed through an online application (CranFlow).

Results

Clinical and laboratorial data of 347 individuals registered from 2008 to 2017 in the Brazilian Database on Craniofacial Anomalies/22q11.2 Deletion Syndrome, were reviewed. They were divided in two groups: (I) 168 individuals investigated before the definition of the criteria and (II) 179 individuals investigated after the criteria application. All of them were investigated for 22q11.2DS by Fluorescent in situ Hybridization (FISH) and/or Multiplex Ligation Probe-dependent Amplification (MLPA), detecting 98 cases with 22q11.2DS. Among the individuals with 22q11.2DS in Group II, 42/53 (79.25%) fulfilled the proposed criteria against 11/53 (20.75%) who did not fulfill them (p < .0001). The association of congenital heart diseases with high predictive value for 22q11.2DS and hypernasal voice were significantly associated to the presence of 22q11.2DS (p = 0.0172 and p < .0001, respectively). In addition, 22q11.2DS was confirmed 3.82 more times when the individuals fulfilled the proposed criteria. Of the 249 cases negative for the typical deletion in 22q11.2, Chromosomal Microarray Analysis (CMA) was performed in 132 individuals and detected pathogenic alterations at other genomic regions in 19 individuals, and variants of uncertain clinical significance in 31 cases.

Conclusions

Therefore, a locus-specific approach could be used to individuals with positive criteria as a cost-effective alternative for 22q11.2DS diagnosis. The authors discuss advantages and suggest ways of implementing this approach to investigate 22q11.2DS in a public health system.
Literature
1.
Swillen A, Vogels A, Devriendt K, Fryns JP. Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am J Med Genet. 2000;97:128–35.CrossRef
2.
Vieira TP, Monteiro FP, Sgardioli IC, Souza J, Fett-Conte AC, Monlleó IL, Fontes MB, Félix TM, Leal GF, Ribeiro EM, Gil-da-Silva-Lopes VL. Clinical features in patients with 22q11.2 deletion syndrome ascertained by palatal abnormalities. Cleft Palate Craniofac J. 2015;52:411–6.CrossRef
3.
Crowley B, Ruffner M, McDonald McGinn DM, Sullivan KE. Variable immune deficiency related to deletion size in chromosome 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2082–6.CrossRef
4.
Unolt M, Versacci P, Anaclerio S, Lambiase C, Calcagni G, Trezzi M, Carotti A, Crowley TB, Zackai EH, Goldmuntz E, et al. Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: from well-established knowledge to new frontiers. Am J Med Genet A. 2018;176:2087–98.CrossRef
5.
Rayannavar A, Levitt Katz LE, Crowley TB, Lessig M, Grand K, Goldmuntz E, Zackai EH, McDonald-McGinn DM. Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2099–103.CrossRef
6.
Swillen A, Moss E, Duijff S. Neurodevelopmental outcome in 22q11.2 deletion syndrome and management. Am J Med Genet A. 2018;176:2160–6.CrossRef
7.
McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, Zackai EH, Emanuel BS, Vermeesch JR, Morrow BE, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.CrossRef
8.
Wu D, Chen Y, Xu C, Wang K, Wang H, Zheng F, Ma D, Wang G. Characteristic face: a key indicator for direct diagnosis of 22q11.2 deletions in Chinese velocardiofacial syndrome patients. PLoS One. 2013;8:e54404.CrossRef
9.
Oh AK, Workman LA, Wong GB. Clinical correlation of chromosome 22q11.2 fluorescent in situ hybridization analysis and velocardiofacial syndrome. Cleft Palate Craniofac J. 2007;44:62–6.CrossRef
10.
Fernandez L, Lapunzina P, Arjona D, Lopez Pajares I, Garcia-Guereta L, Elorza D, Burgueros M, De Torres ML, Mori MA, Palomares M, et al. Comparative study of three diagnostic approaches (FISH, STRs and MLPA) in 30 patients with 22q11.2 deletion syndrome. Clin Genet. 2005;68:373–8.CrossRef
11.
Sgardioli IC, Vieira TP, Simioni M, Monteiro FP, Gil-da-Silva-Lopes VL. 22q11.2 deletion syndrome: laboratory diagnosis and TBX1 and FGF8 mutation screening. J Pediatr Genet. 2015;4:17–22.CrossRef
12.
Driscoll DA, Salvin J, Sellinger B, Budarf ML, McDonald-McGinn DM, Zackai EH, Emanuel BS. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet. 1993;30:813–7.CrossRef
13.
Poirsier C, Besseau-Ayasse J, Schluth-Bolard C, Toutain J, Missirian C, Le Caignec C, Bazin A, de Blois MC, Kuentz P, Catty M, et al. A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH. Eur J Hum Genet. 2015.
14.
Jalali GR, Vorstman JA, Errami A, Vijzelaar R, Biegel J, Shaikh T, Emanuel BS. Detailed analysis of 22q11.2 with a high density MLPA probe set. Hum Mutat. 2008;29:433–40.CrossRef
15.
McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011;90:1–18.CrossRef
16.
Peyvandi S, Lupo PJ, Garbarini J, Woyciechowski S, Edman S, Emanuel BS, Mitchell LE, Goldmuntz E. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases. Pediatr Cardiol. 2013;34:1687–94.CrossRef
17.
Cuturilo G, Drakulic D, Jovanovic I, Krstic A, Djukic M, Skoric D, Mijovic M, Stefanovic I, Milivojevic M, Stevanovic M. Improving the diagnosis of children with 22q11.2 deletion syndrome: a single-center experience from Serbia. Indian Pediatr. 2016;53:786–9.CrossRef
18.
Geddes GC, Basel D, Frommelt P, Kinney A, Earing M. Genetic testing protocol reduces costs and increases rate of genetic diagnosis in infants with congenital heart disease. Pediatr Cardiol. 2017;38:1465–70.CrossRef
19.
Palmer LD, Butcher NJ, Boot E, Hodgkinson KA, Heung T, Chow EWC, Guna A, Crowley TB, Zackai E, McDonald-McGinn DM, Bassett AS. Elucidating the diagnostic odyssey of 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:936–44.CrossRef
20.
Grassi MS, Jacob CM, Kulikowski LD, Pastorino AC, Dutra RL, Miura N, Jatene MB, Pegler SP, Kim CA, Carneiro-Sampaio M. Congenital heart disease as a warning sign for the diagnosis of the 22q11.2 deletion. Arq Bras Cardiol. 2014;103:382–90.PubMedPubMedCentral
21.
Kruszka P, Addissie YA, McGinn DE, Porras AR, Biggs E, Share M, Crowley TB, Chung BH, Mok GT, Mak CC, et al. 22q11.2 deletion syndrome in diverse populations. Am J Med Genet A. 2017;173:879–88.CrossRef
22.
Monteiro FP, Vieira TP, Sgardioli IC, Molck MC, Damiano AP, Souza J, Monlleó IL, Fontes MI, Fett-Conte AC, Félix TM, et al. Defining new guidelines for screening the 22q11.2 deletion based on a clinical and dysmorphologic evaluation of 194 individuals and review of the literature. Eur J Pediatr. 2013;172:927–45.CrossRef
23.
Koczkowska M, Wierzba J, Smigiel R, Sasiadek M, Cabala M, Slezak R, Iliszko M, Kardas I, Limon J, Lipska-Zietkiewicz BS. Genomic findings in patients with clinical suspicion of 22q11.2 deletion syndrome. J Appl Genet. 2017;58:93–8.CrossRef
24.
Volpe-Aquino RM, Monlleó IL, Lustosa-Mendes E, Mora AF, Fett-Conte AC, Félix TM, Xavier AC, Tonocchi R, Ribeiro EM, Pereira R, et al. CranFlow: an application for record-taking and management through the Brazilian database on craniofacial anomalies. Birth Defects Res. 2018;110:72–80.CrossRef
25.
de Souza LC. Phenotype comparison among individuals with developmental delay / intellectual disability with or without genomic imbalances. In: dos Santos AP, Sgardioli IC, Viguetti-Campos NL, JRM P, de Oliveira-Sobrinho RP, Vieira TP, Gil-da-Silva-Lopes VL, editors. Phenotype comparison among individuals with developmental delay / intellectual disability with or without genomic imbalances: J Intellect Disabil Res; 2018.
26.
Hay BN. Deletion 22q11: spectrum of associated disorders. Semin Pediatr Neurol. 2007;14:136–9.CrossRef
27.
Fernandez L, Nevado J, Santos F, Heine-Suner D, Martinez-Glez V, Garcia-Minaur S, Palomo R, Delicado A, Pajares IL, Palomares M, et al. A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review. BMC Med Genet. 2009;10:48.CrossRef
28.
Marques-de-Faria AP, Ferraz VE, Acosta AX, Brunoni D. Clinical genetics in developing countries: the case of Brazil. Community Genet. 2004;7:95–105.PubMed
29.
Horovitz DD, Cardoso MH, Llerena JC, de Mattos RA. Birth defects in Brazil and health care: proposals for public policies in clinical genetics. Cad Saude Publica. 2006;22:2599–609.CrossRef
30.
Monlleó IL, Gil-da-Silva-Lopes VL. Brazil's craniofacial project: genetic evaluation and counseling in the reference network for craniofacial treatment. Cleft Palate Craniofac J. 2006;43:577–9.CrossRef
31.
Castilla EE, Luquetti DV. Brazil: public health genomics. Public Health Genomics. 2009;12:53–8.CrossRef
32.
Monlleo IL, Mossey PA, Gil-da-Silva-Lopes VL. Evaluation of craniofacial care outside the Brazilian reference network for craniofacial treatment. Cleft Palate Craniofac J. 2009;46:204–11.CrossRef
33.
Vieira TP, Sgardioli IC, Gil-da-Silva-Lopes VL. 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. 2013;4:99–106.CrossRef
34.
Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, 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;86:749–64.CrossRef
35.
Jehee FS, Takamori JT, Medeiros PF, Pordeus AC, Latini FR, Bertola DR, Kim CA, Passos-Bueno MR. 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;54:e425–32.CrossRef
36.
Geddes GC, Butterly M, Sajan I. FISH for 22q11.2 deletion not cost-effective for infants with congenital heart disease with microarray. Pediatr Cardiol. 2015;36:531–6.CrossRef
37.
Palmer E, Speirs H, Taylor PJ, Mullan G, Turner G, Einfeld S, Tonge B, Mowat D. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet A. 2014;164A:377–85.CrossRef
Metadata
Title
Testing criteria for 22q11.2 deletion syndrome: preliminary results of a low cost strategy for public health
Authors
Ilária Cristina Sgardioli
Fabíola Paoli Monteiro
Paulo Fanti
Társis Paiva Vieira
Vera Lúcia Gil-da-Silva-Lopes
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1098-1

Other articles of this Issue 1/2019

Orphanet Journal of Rare Diseases 1/2019 Go to the issue

Research

The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan

Research

Late-onset thymidine kinase 2 deficiency: a review of 18 cases

Research

Effects of immunomodulation in classic infantile Pompe patients with high antibody titers

Research

Screening for neuropathic pain in patients with sickle cell disease: is a single assessment scale sufficient?

Research

Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis

Position statement

Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium