Molecular basis of phenylketonuria in Serbia: an update
2023
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Аутори
Klaassen, KristelŠinžar, Ksenija
Stanković, Sara
Đorđević Milošević, Maja
Kecman, Božica
Anđelković, Marina
Skakić, Anita
Spasovski, Vesna
Ugrin, Milena
Komazec, Jovana
Parezanović, Marina
Stevanović, Nina
Pavlović, Sonja
Stojiljković, Maja
Конференцијски прилог (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Introduction: Phenylketonuria (PKU) is the most frequent inborn disorder of amino acid metabolism
caused by variants in human phenylalanine hydroxylase gene (PAH).
Methods: In thisstudy (an update for the time period of 10 years, with patientsfrom our previousstudies included) a total of 109 PKU patients from Serbia were analyzed. They were classified into three phenotypic categories in accordance with pre-treatment plasma phenylalanine level: classic PKU, mild PKU
and mild hyperphenylalaninemia. For genetic analyses, we combined Sanger sequencing, MLPA and
next generation sequencing to identify disease-causing variantsin PAH gene, which were further classified using ACMG classification. Additionally, we used in silico and/or eukaryotic expression studiesto assess the effect of novel genetic variants identified in our patients.
Results: Disease-causing variants were identified in 217 of 218 alleles, reaching detection rate of 99.5%.
We detected a total of 32 different variants, o...f which 29 previously described and three novel ones:
p.Gln226Lys, p.Pro244His and p.Pro416Leu. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. The most frequent variant was p.Leu48Ser (31.2%), followed
by p.Arg408Trp (13.8%), p.Ile306Val (9.2%). p.Glu390Gly (5%), p.Pro281Leu (4.6%), and p.Arg261Gln
(3.2%). All detected disease-causing variants were classified as pathogenic using ACMG classification.
Conclusion: Our study brings the updated spectrum of molecular genetic data, variant classification
and detailed phenotypic characteristicsfor PKU patientsfrom Serbia. Therefore, ourstudy contributesto
better understanding of molecular landscape of PKU in Europe and to general knowledge on genotype–
phenotype correlation in PKU.
Кључне речи:
phenylketonuria / phenylalanine hydroxylase / variant / genotype-phenotype correlationИзвор:
CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia, 2023, 93-93Издавач:
- Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
Финансирање / пројекти:
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Klaassen, Kristel AU - Šinžar, Ksenija AU - Stanković, Sara AU - Đorđević Milošević, Maja AU - Kecman, Božica AU - Anđelković, Marina AU - Skakić, Anita AU - Spasovski, Vesna AU - Ugrin, Milena AU - Komazec, Jovana AU - Parezanović, Marina AU - Stevanović, Nina AU - Pavlović, Sonja AU - Stojiljković, Maja PY - 2023 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2142 AB - Introduction: Phenylketonuria (PKU) is the most frequent inborn disorder of amino acid metabolism caused by variants in human phenylalanine hydroxylase gene (PAH). Methods: In thisstudy (an update for the time period of 10 years, with patientsfrom our previousstudies included) a total of 109 PKU patients from Serbia were analyzed. They were classified into three phenotypic categories in accordance with pre-treatment plasma phenylalanine level: classic PKU, mild PKU and mild hyperphenylalaninemia. For genetic analyses, we combined Sanger sequencing, MLPA and next generation sequencing to identify disease-causing variantsin PAH gene, which were further classified using ACMG classification. Additionally, we used in silico and/or eukaryotic expression studiesto assess the effect of novel genetic variants identified in our patients. Results: Disease-causing variants were identified in 217 of 218 alleles, reaching detection rate of 99.5%. We detected a total of 32 different variants, of which 29 previously described and three novel ones: p.Gln226Lys, p.Pro244His and p.Pro416Leu. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. The most frequent variant was p.Leu48Ser (31.2%), followed by p.Arg408Trp (13.8%), p.Ile306Val (9.2%). p.Glu390Gly (5%), p.Pro281Leu (4.6%), and p.Arg261Gln (3.2%). All detected disease-causing variants were classified as pathogenic using ACMG classification. Conclusion: Our study brings the updated spectrum of molecular genetic data, variant classification and detailed phenotypic characteristicsfor PKU patientsfrom Serbia. Therefore, ourstudy contributesto better understanding of molecular landscape of PKU in Europe and to general knowledge on genotype– phenotype correlation in PKU. PB - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade C3 - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia T1 - Molecular basis of phenylketonuria in Serbia: an update EP - 93 SP - 93 UR - https://hdl.handle.net/21.15107/rcub_imagine_2142 ER -
@conference{ author = "Klaassen, Kristel and Šinžar, Ksenija and Stanković, Sara and Đorđević Milošević, Maja and Kecman, Božica and Anđelković, Marina and Skakić, Anita and Spasovski, Vesna and Ugrin, Milena and Komazec, Jovana and Parezanović, Marina and Stevanović, Nina and Pavlović, Sonja and Stojiljković, Maja", year = "2023", abstract = "Introduction: Phenylketonuria (PKU) is the most frequent inborn disorder of amino acid metabolism caused by variants in human phenylalanine hydroxylase gene (PAH). Methods: In thisstudy (an update for the time period of 10 years, with patientsfrom our previousstudies included) a total of 109 PKU patients from Serbia were analyzed. They were classified into three phenotypic categories in accordance with pre-treatment plasma phenylalanine level: classic PKU, mild PKU and mild hyperphenylalaninemia. For genetic analyses, we combined Sanger sequencing, MLPA and next generation sequencing to identify disease-causing variantsin PAH gene, which were further classified using ACMG classification. Additionally, we used in silico and/or eukaryotic expression studiesto assess the effect of novel genetic variants identified in our patients. Results: Disease-causing variants were identified in 217 of 218 alleles, reaching detection rate of 99.5%. We detected a total of 32 different variants, of which 29 previously described and three novel ones: p.Gln226Lys, p.Pro244His and p.Pro416Leu. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. The most frequent variant was p.Leu48Ser (31.2%), followed by p.Arg408Trp (13.8%), p.Ile306Val (9.2%). p.Glu390Gly (5%), p.Pro281Leu (4.6%), and p.Arg261Gln (3.2%). All detected disease-causing variants were classified as pathogenic using ACMG classification. Conclusion: Our study brings the updated spectrum of molecular genetic data, variant classification and detailed phenotypic characteristicsfor PKU patientsfrom Serbia. Therefore, ourstudy contributesto better understanding of molecular landscape of PKU in Europe and to general knowledge on genotype– phenotype correlation in PKU.", publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade", journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia", title = "Molecular basis of phenylketonuria in Serbia: an update", pages = "93-93", url = "https://hdl.handle.net/21.15107/rcub_imagine_2142" }
Klaassen, K., Šinžar, K., Stanković, S., Đorđević Milošević, M., Kecman, B., Anđelković, M., Skakić, A., Spasovski, V., Ugrin, M., Komazec, J., Parezanović, M., Stevanović, N., Pavlović, S.,& Stojiljković, M.. (2023). Molecular basis of phenylketonuria in Serbia: an update. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 93-93. https://hdl.handle.net/21.15107/rcub_imagine_2142
Klaassen K, Šinžar K, Stanković S, Đorđević Milošević M, Kecman B, Anđelković M, Skakić A, Spasovski V, Ugrin M, Komazec J, Parezanović M, Stevanović N, Pavlović S, Stojiljković M. Molecular basis of phenylketonuria in Serbia: an update. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:93-93. https://hdl.handle.net/21.15107/rcub_imagine_2142 .
Klaassen, Kristel, Šinžar, Ksenija, Stanković, Sara, Đorđević Milošević, Maja, Kecman, Božica, Anđelković, Marina, Skakić, Anita, Spasovski, Vesna, Ugrin, Milena, Komazec, Jovana, Parezanović, Marina, Stevanović, Nina, Pavlović, Sonja, Stojiljković, Maja, "Molecular basis of phenylketonuria in Serbia: an update" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):93-93, https://hdl.handle.net/21.15107/rcub_imagine_2142 .