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DOI: 10.1055/s-0042-1751268
Impact of Deletion on Angelman Syndrome Phenotype Variability: Phenotype–Genotype Correlation in 97 Patients with Motor Developmental Delay
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Abstract
Angelman syndrome (AS) is a rare neurodevelopmental disorder due to genetic defects involving chromosome 15, known by intellectual disability, cognitive and behavioral disorders, ataxia, delayed motor development, and seizures. This study highlights the clinical spectrum and molecular research to establish the genotype–phenotype correlation in the pediatric Moroccan population. Methylation-specific-polymerase chain reaction (MS-PCR) is a primordial technique not only to identify the genetic mechanism of AS but also to characterize the different molecular classes induced in the appearance of the clinical symptoms. Patients with positive methylation profile were additionally studied by fluorescent in situ hybridization. Sequencing analysis of the UBE3A gene was performed for patients with negative MS-PCR. We used Fisher's test to assess differences in the distribution of features frequencies among the deletional and the nondeletional group. Statistical analysis was performed using R project. We identified from 97 patients diagnosed with AS, 14 (2.06%) had a classical AS phenotype, while 70 (84.5%) patients displayed a subset of consistent and frequent criteria. Development delay was shown severe in 63% and moderate in 37%. Nineteen out of 97 of them had MS-PCR positive in which 17 (89.47%) had 15q11-q13 deletion. Deletion patients presented a higher incidence of epileptic seizures (p = 0.04), ataxia (p = 0.0008), and abnormal electroencephalogram (EEG) profile (p = 0.003). We further found out a frameshift deletion located at exon 9 of the UBE3A gene discovered in a 5 years old patient. We report in this study the genotype–phenotype correlation using different molecular testing. Correlation analysis did not reveal any statistical differences in phenotypic dissimilarity between deletion and nondeletion groups for most clinical features, except the correlation was highly significant in the abnormal EEG. According to our findings, we recommend offering MS-PCR analysis to all patients with severe intellectual disability, developmental delay, speech impairment, happy demeanor, and hypopigmentation.
Publication History
Received: 20 September 2021
Accepted: 23 May 2022
Article published online:
16 August 2022
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References
- 1 Kalsner L, Chamberlain SJ. Prader-Willi, Angelman, and 15q11-q13 duplication syndromes. Pediatr Clin North Am 2015; 62 (03) 587-606
- 2 Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997; 15 (01) 70-73
- 3 Tan W-H, Bird LM. Angelman syndrome: current and emerging therapies in 2016. Am J Med Genet C Semin Med Genet 2016; 172 (04) 384-401
- 4 Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman syndrome. Neurotherapeutics 2015; 12 (03) 641-650
- 5 Williams CA, Beaudet AL, Clayton-Smith J. et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A 2006; 140 (05) 413-418
- 6 Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med 2012; 14 (01) 10-26
- 7 Williams CA, Angelman H, Clayton-Smith J. et al; Angelman Syndrome Foundation. Angelman syndrome: consensus for diagnostic criteria. Am J Med Genet 1995; 56 (02) 237-238
- 8 Luk HM, Lo IFM. Angelman syndrome in Hong Kong Chinese: a 20 years' experience. Eur J Med Genet 2016; 59 (6-7): 315-319
- 9 Guerrini R, Carrozzo R, Rinaldi R, Bonanni P. Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms. Paediatr Drugs 2003; 5 (10) 647-661
- 10 Buchholz T, Jackson J, Robson L, Smith A. Evaluation of methylation analysis for diagnostic testing in 258 referrals suspected of Prader-Willi or Angelman syndromes. Hum Genet 1998; 103 (05) 535-539
- 11 Christian SL, Robinson WP, Huang B. et al. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. Am J Hum Genet 1995; 57 (01) 40-48
- 12 Van Buggenhout GJ, Descheemaeker MJ, Thiry P, Trommelen JC, Hamel BC, Fryns JP. Angelman syndrome in three adult patients with atypical presentation and severe neurological complications. Genet Couns 2000; 11 (04) 363-373
- 13 Bai J-L, Qu Y-J, Jin Y-W. et al. Molecular and clinical characterization of Angelman syndrome in Chinese patients. Clin Genet 2014; 85 (03) 273-277
- 14 Varela MC, Kok F, Otto PA, Koiffmann CP. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet 2004; 12 (12) 987-992
- 15 Liu C, Zhang X, Wang J. et al. Genetic testing for Prader-Willi syndrome and Angelman syndrome in the clinical practice of Guangdong Province, China. [Internet]. Mol Cytogenet 2019; 12: 7 . cited 2020May20. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378742/
- 16 Sadikovic B, Fernandes P, Zhang VW. et al. Mutation Update for UBE3A variants in Angelman syndrome. Hum Mutat 2014; 35 (12) 1407-1417
- 17 Lossie AC, Whitney MM, Amidon D. et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001; 38 (12) 834-845
- 18 Horsler K, Oliver C. The behavioural phenotype of Angelman syndrome. J Intellect Disabil Res 2006; 50 (Pt 1): 33-53
- 19 Chai J-H, Locke DP, Greally JM. et al. Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet 2003; 73 (04) 898-925
- 20 Dagli A, Buiting K, Williams CA. Molecular and clinical aspects of Angelman syndrome. Mol Syndromol 2012; 2 (3-5): 100-112
- 21 Manoubi W, Rouissi A, Hmida D. et al. Screening of Angelman syndrome deletion and methylation aberration using MS-MLPA assay in a Tunisian population. Biomed Res Clin Pract 2019;4. Available at: https://www.oatext.com/screening-of-angelman-syndrome-deletion-and-methylation-aberration-using-ms-mlpa-assay-in-a-tunisian-population.php
- 22 Smith A, Marks R, Haan E, Dixon J, Trent RJ. Clinical features in four patients with Angelman syndrome resulting from paternal uniparental disomy. J Med Genet 1997; 34 (05) 426-429