Abstract
Aim: Genomic imprinting disorders are a group of disorders caused by a parental imprinting mechanism that disappears with various genetic alterations. The most common of these disorders are Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome and Silver-Russell syndrome. The aim of this study was to comprehensively analyze the clinical manifestations and genetic outcomes of patients with genomic imprinting disorders.
Materials and Methods: Our study included 28 patients diagnosed with imprinting disorder between 2021 and 2024. DNA was isolated from peripheral blood samples obtained from the patients and methylation-specific MLPA was performed.
Results: In the present study, 28 patients were included for analysis. Thirteen patients were diagnosed with Prader-Willi syndrome (PWS), eight with Angelman syndrome, three with Beckwith-Wiedemann syndrome, and four with Silver-Russell syndrome. The results of genetic tests were analyzed, revealing a deletion in the chromosome 15q11 region in six of the 13 patients with PWS and a PWS-specific methylation pattern in seven of them. In the cohort of patients diagnosed with Angelman syndrome, seven cases were found to have a deletion in the chromosome 15q11 region, while one patient exhibited an Angelman syndrome-specific methylation pattern. H19 hypomethylation was identified in all patients with Silver-Russell syndrome, and H19 hypermethylation and KCNQ1OT1 hypomethylation were observed in all patients with Beckwith-Wiedemann syndrome. An evaluation of the clinical findings of the patients revealed the presence of selective IgA deficiency, retinal dystrophy, and hearing loss in patients with Prader-Willi syndrome, which has not been previously reported. Furthermore, the prevalence of congenital cardiac anomalies and sleep apnea was found to be higher in this patient group compared to the literature.
Conclusion: The intricate epigenetic mechanisms underlying genomic imprinting disorders, the variability in patient presentations, and the subtlety of the findings contribute to the complexity of the diagnostic process. We believe that our study will contribute to the literature in terms of rare clinical manifestations and genetic consequences of imprinting disorders.
References
- Wang SE, Jiang YH. Novel epigenetic molecular therapies for imprinting disorders. Mol Psychiatry. Ağustos 2023;28(8):3182-93.
- Eggermann T, Monk D, de Nanclares GP, Kagami M, Giabicani E, Riccio A, vd. Imprinting disorders. Nat Rev Dis Primer. 29 Haziran 2023;9(1):33.
- Ishida M, Moore GE. The role of imprinted genes in humans. Mol Aspects Med. 2013;34(4):826-40.
- Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.
- Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med Off J Am Coll Med Genet. Ocak 2012;14(1):10-26.
- Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 23 Aralık 2024]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1330/
- Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman Syndrome. Neurother J Am Soc Exp Neurother. Temmuz 2015;12(3):641-50.
- Maranga C, Fernandes TG, Bekman E, da Rocha ST. Angelman syndrome: a journey through the brain. FEBS J. Haziran 2020;287(11):2154-75.
- Yang L, Shu X, Mao S, Wang Y, Du X, Zou C. Genotype-Phenotype Correlations in Angelman Syndrome. Genes. 28 Haziran 2021;12(7):987.
- Wakeling EL. Silver-Russell syndrome. Arch Dis Child. Aralık 2011;96(12):1156-61.
- Saal HM, Harbison MD, Netchine I. Silver-Russell Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 23 Aralık 2024]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1324/
- Karaman S, Hazan F, Erdem SB, Gülez N, Genel F. Do microdeletions lead to immune deficiency? Cent-Eur J Immunol. 2020;45(1):69-72.
- Gul Y, Kapaklı H, Aytekin SE, Guner ŞN, Keles S, Zamani AG, vd. Evaluation of immunological abnormalities in patients with rare syndromes. Central-European journal of immunology, 2022 ;47(4), 299–307. https://doi.org/10.5114/ceji.2022.124080
- Aghamohammadi A, Abolhassani H, Biglari M, Abolmaali S, Moazzami K, Tabatabaeiyan M, vd. Analysis of switched memory B cells in patients with IgA deficiency. International archives of allergy and immunology, 2011;156(4), 462–468. https://doi.org/10.1159/000323903
- Torrado M, Foncuberta ME, Perez MF de C, Gravina LP, Araoz HV, Baialardo E, vd. Change in prevalence of congenital defects in children with Prader-Willi syndrome. Pediatrics. Şubat 2013;131(2):e544-549.
- Debs R, Diene G, Cortadellas J, Molinas C, Kermorgant M, Tauber M, vd. Cardiovascular autonomic dysfunction and sleep abnormalities in children with Prader-Willi syndrome. Clin Auton Res Off J Clin Auton Res Soc. 04 Aralık 2024;
- Bohonowych JE, Vrana-Diaz CJ, Miller JL, McCandless SE, Strong TV. Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry. BMC Ophthalmol. 12 Ağustos 2021;21:296.
- Bouchlarhem S, Achraf S, Drissia B, Adil E, Azeddine L, Fahd EAEI. Congenital deafness: from screening to management. Annals of medicine and surgery 2012; 87(6), 3236–3243. https://doi.org/10.1097/MS9.0000000000002637
- Nebbioso M, Artico M, Gharbiya M, Mannocci A, Limoli PG, Iannetta D, vd. State of the Art on Inherited Retinal Dystrophies: Management and Molecular Genetics. Journal of clinical medicine, 2025;14(10), 3526. https://doi.org/10.3390/jcm14103526
- Cintra HA, Rocha DN, da Costa ACC, Tyszler LS, Freitas S, de Araujo LA, vd. Investigating the correlation between genotype and phenotype in Prader-Willi syndrome: a study of 45 cases from Brazil. Orphanet J Rare Dis. 20 Haziran 2024;19:240.
- Jana NR. Understanding the pathogenesis of Angelman syndrome through animal models. Neural Plast. 2012;2012:710943.
- Madaan M, Mendez MD. Angelman Syndrome. Içinde: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [a.yer 04 Şubat 2025]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK560870/
- Wang KH, Kupa J, Duffy KA, Kalish JM. Diagnosis and Management of Beckwith-Wiedemann Syndrome. Front Pediatr. 21 Ocak 2020;7:562.
- Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 04 Şubat 2025]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1394/
- Beygo J, Russo S, Tannorella P, Santen GWE, Dufke A, Schlaich E, vd. Prenatal testing for imprinting disorders: A laboratory perspective. Prenatal diagnosis. 2023;43(8),973–982. https://doi.org/10.1002/pd.6398
- Russo S, Calzari L, Mussa A, Mainini E, Cassina M, Di Candia S, vd. A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes. Clinical epigenetics, 2016;8,23. https://doi.org/10.1186/s13148-016-0183-8
Abstract
Amaç: Genomik imprinting bozukluklar, çeşitli genetik değişikliklerle birlikte ortadan kalkan ebeveyne özgü baskılama mekanizmasının neden olduğu hastalıklar grubudur. Bu hastalıklar arasında en sık Prader-Willi sendromu, Angelman sendromu, Beckwith-Wiedemann sendromu ve Silver-Russell sendromu yer almaktadır. Bu çalışmanın amacı, genomik imprinting bozukluklarda meydana gelen klinik bulguları ve hastaların genetik sonuçlarını kapsamlı bir şekilde incelemektir.
Gereç ve Yöntem: Çalışmamıza 2021-2024 yılları arasında imprinting bozukluk tanısı almış 28 hasta dahil edildi. Hastalardan alınan periferik kan örneklerinden DNA izolasyonu yapılarak metilasyon spesifik MLPA çalışması gerçekleştirildi.
Bulgular: Çalışmamıza dahil edilen 28 hastanın 13’ü Prader-Willi sendromu (PWS), sekizi Angelman sendromu, üçü Beckwith-Wiedemann sendromu, dördü ise Silver-Russell sendromu tanısı almıştı. Genetik tetkik sonuçları incelendiğinde, PWS tanılı 13 hastanın altısında kromozom 15q11 bölgesinde delesyon yedisinde ise PWS spesifik metilasyon paterni tespit edildi. Angelman sendromlu hastaların yedisinde kromozom 15q11 bölgesinde delesyon, bir hastada ise Angelman sendromu spesifik metilasyon paterni izlendi. Silver-Russell sendromlu hastaların tamamında H19 hipometilasyonu, Beckwith-Wiedemann sendromlu hastaların tamamında ise H19 hipermetilasyonu ve KCNQ1OT1 hipometilasyonu saptandı. Hastaların klinik bulgularını değerlendirdiğimizde ise Prader-Willi sendromlu hastalarda daha önce bildirilmeyen selektif IgA eksikliği, retinal distrofi ve işitme kaybı bulgularını gözlemledik. Ayrıca PWS grubunda konjenital kardiyak anomali ve uyku apnesi sıklığı literatüre göre daha fazlaydı.
Sonuç: Genomik imprinting bozuklukların altında yatan karmaşık epigenetik mekanizmalar, hastalar arasındaki fenotipik değişkenlikler ve silik bulgular hastalığın tanısını zorlaştırmaktadır. Çalışmamızın imprinting bozuklukların nadir görülen klinik bulguları ve genetik sonuçları açısından literatüre katkı sağlayacağını düşünmekteyiz.
Ethical Statement
Çalışmamız Başakşehir Çam ve Sakura Şehir Hastanesi etik kurulu onayını almıştır.
Supporting Institution
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Thanks
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References
- Wang SE, Jiang YH. Novel epigenetic molecular therapies for imprinting disorders. Mol Psychiatry. Ağustos 2023;28(8):3182-93.
- Eggermann T, Monk D, de Nanclares GP, Kagami M, Giabicani E, Riccio A, vd. Imprinting disorders. Nat Rev Dis Primer. 29 Haziran 2023;9(1):33.
- Ishida M, Moore GE. The role of imprinted genes in humans. Mol Aspects Med. 2013;34(4):826-40.
- Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.
- Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med Off J Am Coll Med Genet. Ocak 2012;14(1):10-26.
- Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 23 Aralık 2024]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1330/
- Margolis SS, Sell GL, Zbinden MA, Bird LM. Angelman Syndrome. Neurother J Am Soc Exp Neurother. Temmuz 2015;12(3):641-50.
- Maranga C, Fernandes TG, Bekman E, da Rocha ST. Angelman syndrome: a journey through the brain. FEBS J. Haziran 2020;287(11):2154-75.
- Yang L, Shu X, Mao S, Wang Y, Du X, Zou C. Genotype-Phenotype Correlations in Angelman Syndrome. Genes. 28 Haziran 2021;12(7):987.
- Wakeling EL. Silver-Russell syndrome. Arch Dis Child. Aralık 2011;96(12):1156-61.
- Saal HM, Harbison MD, Netchine I. Silver-Russell Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 23 Aralık 2024]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1324/
- Karaman S, Hazan F, Erdem SB, Gülez N, Genel F. Do microdeletions lead to immune deficiency? Cent-Eur J Immunol. 2020;45(1):69-72.
- Gul Y, Kapaklı H, Aytekin SE, Guner ŞN, Keles S, Zamani AG, vd. Evaluation of immunological abnormalities in patients with rare syndromes. Central-European journal of immunology, 2022 ;47(4), 299–307. https://doi.org/10.5114/ceji.2022.124080
- Aghamohammadi A, Abolhassani H, Biglari M, Abolmaali S, Moazzami K, Tabatabaeiyan M, vd. Analysis of switched memory B cells in patients with IgA deficiency. International archives of allergy and immunology, 2011;156(4), 462–468. https://doi.org/10.1159/000323903
- Torrado M, Foncuberta ME, Perez MF de C, Gravina LP, Araoz HV, Baialardo E, vd. Change in prevalence of congenital defects in children with Prader-Willi syndrome. Pediatrics. Şubat 2013;131(2):e544-549.
- Debs R, Diene G, Cortadellas J, Molinas C, Kermorgant M, Tauber M, vd. Cardiovascular autonomic dysfunction and sleep abnormalities in children with Prader-Willi syndrome. Clin Auton Res Off J Clin Auton Res Soc. 04 Aralık 2024;
- Bohonowych JE, Vrana-Diaz CJ, Miller JL, McCandless SE, Strong TV. Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry. BMC Ophthalmol. 12 Ağustos 2021;21:296.
- Bouchlarhem S, Achraf S, Drissia B, Adil E, Azeddine L, Fahd EAEI. Congenital deafness: from screening to management. Annals of medicine and surgery 2012; 87(6), 3236–3243. https://doi.org/10.1097/MS9.0000000000002637
- Nebbioso M, Artico M, Gharbiya M, Mannocci A, Limoli PG, Iannetta D, vd. State of the Art on Inherited Retinal Dystrophies: Management and Molecular Genetics. Journal of clinical medicine, 2025;14(10), 3526. https://doi.org/10.3390/jcm14103526
- Cintra HA, Rocha DN, da Costa ACC, Tyszler LS, Freitas S, de Araujo LA, vd. Investigating the correlation between genotype and phenotype in Prader-Willi syndrome: a study of 45 cases from Brazil. Orphanet J Rare Dis. 20 Haziran 2024;19:240.
- Jana NR. Understanding the pathogenesis of Angelman syndrome through animal models. Neural Plast. 2012;2012:710943.
- Madaan M, Mendez MD. Angelman Syndrome. Içinde: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [a.yer 04 Şubat 2025]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK560870/
- Wang KH, Kupa J, Duffy KA, Kalish JM. Diagnosis and Management of Beckwith-Wiedemann Syndrome. Front Pediatr. 21 Ocak 2020;7:562.
- Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann Syndrome. Içinde: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editörler. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [a.yer 04 Şubat 2025]. Erişim adresi: http://www.ncbi.nlm.nih.gov/books/NBK1394/
- Beygo J, Russo S, Tannorella P, Santen GWE, Dufke A, Schlaich E, vd. Prenatal testing for imprinting disorders: A laboratory perspective. Prenatal diagnosis. 2023;43(8),973–982. https://doi.org/10.1002/pd.6398
- Russo S, Calzari L, Mussa A, Mainini E, Cassina M, Di Candia S, vd. A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes. Clinical epigenetics, 2016;8,23. https://doi.org/10.1186/s13148-016-0183-8
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Medical Genetics (Excl. Cancer Genetics) |
| Journal Section | Research Article |
| Authors | |
| Submission Date | February 11, 2025 |
| Acceptance Date | November 4, 2025 |
| Publication Date | March 9, 2026 |
| DOI | https://doi.org/10.19161/etd.1637605 |
| IZ | https://izlik.org/JA83WP88EN |
| Published in Issue | Year 2026 Volume: 65 Issue: 1 |
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