<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective:</bold> The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations.<bold>Material and Methods:</bold> In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene.<bold>Results:</bold> In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T > C; p.Leu163Ser and c.1832A > T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4.<bold>Conclusion:</bold> The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.</abstract>

Objective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations.Material and Methods: In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene.Results: In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T > C; p.Leu163Ser and c.1832A > T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4.Conclusion: The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.

Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

Department of Medical Chemistry and Biochemistry, Medical Faculty

AND Genetic Medico-Diagnostic Laboratory “Genica”

Department of Medical Ethics and Law, Faculty of Public Health

Children’s Hospital “Prof. Ivan Mitev MD”, Department of Endocrinological and Genetic Diseases, Medical Faculty

Acta Medica Bulgarica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Objective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe...

Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

Publié en ligne: 21 mai 2020

Pages: 9 - 16

Reçu: 01 mai 2019

Accepté: 01 juin 2019

DOI: https://doi.org/10.2478/amb-2020-0002

Mots clés
Angelman syndrome, UBE3A, imprinting center, CpG methylation, 15q11.2-q13, paternal UPD

© 2018 B. Georgieva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

Publié en ligne: 21 mai 2020

Pages: 9 - 16

Reçu: 01 mai 2019

Accepté: 01 juin 2019

DOI: https://doi.org/10.2478/amb-2020-0002

Mots clésAngelman syndrome, UBE3A, imprinting center, CpG methylation, 15q11.2-q13, paternal UPD

© 2018 B. Georgieva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Mots clés
Angelman syndrome, UBE3A, imprinting center, CpG methylation, 15q11.2-q13, paternal UPD