WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib
Authors
Skakić, AnitaParezanović, Marina
Pavlović, Đorđe
Srevanović, Nina
Anđelković, Marina
Klaassen, Kristel
Ugrin, Milena
Komazec, Jovana
Spasovski, Vesna
Đorđević, Maja
Pavlović, Sonja
Stojiljković, Maja
Contributors
Morić, IvanaĐorđević, Valentina
Conference object (Published version)
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Show full item recordAbstract
University of Belgrade, Serbia
anita.skakic@imgge.bg.ac.rs
Glycogen Storage Disease Ib (GSD Ib) is a rare metabolic disorder characterized by a deficiency
of glucose-6-phosphate translocase, leading to metabolic disruptions and neutropenia.
Varying severity and progression of neutropenia were detected among individuals with the
same genotype, indicating a complex genotype-phenotype correlation. We aim to explore
potential modifier genes influencing neutropenia in GSD Ib, focusing on five patients with
the homozygous c.1042_1043delCT variant in the SLC37A4 gene. These patients exhibit
diverse neutropenia profiles, with two displaying mild and intermittent neutropenia, while
the remaining three develop severe and persistent neutropenia.
Whole genome sequencing (MGISEQ-G400, BGITech) was conducted on five unrelated
subjects, all presenting with previously identified pathogenic homozygous SLC37A4 variant.
We followed GATK best practices for genomic data processing to identify g...enetic variations
associated with observed clinical differences. A unique pipeline was constructed focusing
on neutropenia-related genes and genes involved in glucose-6-phosphate metabolism,
neutrophil function pathways, immune system regulation, ER stress, and UPR response.
In patients with severe neutropenia, we identified two heterozygous variants (c.-70G>C and
c.96T>C, p.Thr32Thr) in the JAGN1 gene, which is essential for neutrophil differentiation.
Additionally, severe neutropenia patients had variants in CTLA4 (c.49A>G, p.Thr17Ala) and
TGFB1 (c.29C>T, p.Pro10Leu), genes involved in immune regulation and cell survival and which
have previously been recognized as modifier genes in various immunological conditions.
This research underscores the potential significance of modifier genes in shaping the diverse
course of neutropenia in GSD Ib, highlighting the need for further functional studies to
elucidate the precise roles of these variants in disease presentation. Investigating potential
genetic modifiers can provide valuable insights into the molecular base of the disease and
guide future research focused on developing customized therapeutic approaches for the
specific neutropenic phenotype.
Keywords:
GSD Ib / WGS / modifier genesSource:
5th Belgrade Bioinformatics Conference, 2024, 72-72Publisher:
- Belgrade : Institute of Molecular Genetics and Genetic Engineering
Funding / projects:
- GlucoAdjust - New concept for treatment of glycogen storage disease Ib and diabetes mellitus type 2: small molecule compounds able to adjust glucose level through binding glucose-6-phospate translocase (RS-ScienceFundRS-Prizma2023_PM-6999)
Note:
- Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024.
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Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Skakić, Anita AU - Parezanović, Marina AU - Pavlović, Đorđe AU - Srevanović, Nina AU - Anđelković, Marina AU - Klaassen, Kristel AU - Ugrin, Milena AU - Komazec, Jovana AU - Spasovski, Vesna AU - Đorđević, Maja AU - Pavlović, Sonja AU - Stojiljković, Maja PY - 2024 UR - www.belbi.bg.ac.rs UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2457 AB - University of Belgrade, Serbia anita.skakic@imgge.bg.ac.rs Glycogen Storage Disease Ib (GSD Ib) is a rare metabolic disorder characterized by a deficiency of glucose-6-phosphate translocase, leading to metabolic disruptions and neutropenia. Varying severity and progression of neutropenia were detected among individuals with the same genotype, indicating a complex genotype-phenotype correlation. We aim to explore potential modifier genes influencing neutropenia in GSD Ib, focusing on five patients with the homozygous c.1042_1043delCT variant in the SLC37A4 gene. These patients exhibit diverse neutropenia profiles, with two displaying mild and intermittent neutropenia, while the remaining three develop severe and persistent neutropenia. Whole genome sequencing (MGISEQ-G400, BGITech) was conducted on five unrelated subjects, all presenting with previously identified pathogenic homozygous SLC37A4 variant. We followed GATK best practices for genomic data processing to identify genetic variations associated with observed clinical differences. A unique pipeline was constructed focusing on neutropenia-related genes and genes involved in glucose-6-phosphate metabolism, neutrophil function pathways, immune system regulation, ER stress, and UPR response. In patients with severe neutropenia, we identified two heterozygous variants (c.-70G>C and c.96T>C, p.Thr32Thr) in the JAGN1 gene, which is essential for neutrophil differentiation. Additionally, severe neutropenia patients had variants in CTLA4 (c.49A>G, p.Thr17Ala) and TGFB1 (c.29C>T, p.Pro10Leu), genes involved in immune regulation and cell survival and which have previously been recognized as modifier genes in various immunological conditions. This research underscores the potential significance of modifier genes in shaping the diverse course of neutropenia in GSD Ib, highlighting the need for further functional studies to elucidate the precise roles of these variants in disease presentation. Investigating potential genetic modifiers can provide valuable insights into the molecular base of the disease and guide future research focused on developing customized therapeutic approaches for the specific neutropenic phenotype. PB - Belgrade : Institute of Molecular Genetics and Genetic Engineering C3 - 5th Belgrade Bioinformatics Conference T1 - WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib EP - 72 SP - 72 UR - https://hdl.handle.net/21.15107/rcub_imagine_2457 ER -
@conference{ author = "Skakić, Anita and Parezanović, Marina and Pavlović, Đorđe and Srevanović, Nina and Anđelković, Marina and Klaassen, Kristel and Ugrin, Milena and Komazec, Jovana and Spasovski, Vesna and Đorđević, Maja and Pavlović, Sonja and Stojiljković, Maja", year = "2024", abstract = "University of Belgrade, Serbia anita.skakic@imgge.bg.ac.rs Glycogen Storage Disease Ib (GSD Ib) is a rare metabolic disorder characterized by a deficiency of glucose-6-phosphate translocase, leading to metabolic disruptions and neutropenia. Varying severity and progression of neutropenia were detected among individuals with the same genotype, indicating a complex genotype-phenotype correlation. We aim to explore potential modifier genes influencing neutropenia in GSD Ib, focusing on five patients with the homozygous c.1042_1043delCT variant in the SLC37A4 gene. These patients exhibit diverse neutropenia profiles, with two displaying mild and intermittent neutropenia, while the remaining three develop severe and persistent neutropenia. Whole genome sequencing (MGISEQ-G400, BGITech) was conducted on five unrelated subjects, all presenting with previously identified pathogenic homozygous SLC37A4 variant. We followed GATK best practices for genomic data processing to identify genetic variations associated with observed clinical differences. A unique pipeline was constructed focusing on neutropenia-related genes and genes involved in glucose-6-phosphate metabolism, neutrophil function pathways, immune system regulation, ER stress, and UPR response. In patients with severe neutropenia, we identified two heterozygous variants (c.-70G>C and c.96T>C, p.Thr32Thr) in the JAGN1 gene, which is essential for neutrophil differentiation. Additionally, severe neutropenia patients had variants in CTLA4 (c.49A>G, p.Thr17Ala) and TGFB1 (c.29C>T, p.Pro10Leu), genes involved in immune regulation and cell survival and which have previously been recognized as modifier genes in various immunological conditions. This research underscores the potential significance of modifier genes in shaping the diverse course of neutropenia in GSD Ib, highlighting the need for further functional studies to elucidate the precise roles of these variants in disease presentation. Investigating potential genetic modifiers can provide valuable insights into the molecular base of the disease and guide future research focused on developing customized therapeutic approaches for the specific neutropenic phenotype.", publisher = "Belgrade : Institute of Molecular Genetics and Genetic Engineering", journal = "5th Belgrade Bioinformatics Conference", title = "WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib", pages = "72-72", url = "https://hdl.handle.net/21.15107/rcub_imagine_2457" }
Skakić, A., Parezanović, M., Pavlović, Đ., Srevanović, N., Anđelković, M., Klaassen, K., Ugrin, M., Komazec, J., Spasovski, V., Đorđević, M., Pavlović, S.,& Stojiljković, M.. (2024). WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib. in 5th Belgrade Bioinformatics Conference Belgrade : Institute of Molecular Genetics and Genetic Engineering., 72-72. https://hdl.handle.net/21.15107/rcub_imagine_2457
Skakić A, Parezanović M, Pavlović Đ, Srevanović N, Anđelković M, Klaassen K, Ugrin M, Komazec J, Spasovski V, Đorđević M, Pavlović S, Stojiljković M. WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib. in 5th Belgrade Bioinformatics Conference. 2024;:72-72. https://hdl.handle.net/21.15107/rcub_imagine_2457 .
Skakić, Anita, Parezanović, Marina, Pavlović, Đorđe, Srevanović, Nina, Anđelković, Marina, Klaassen, Kristel, Ugrin, Milena, Komazec, Jovana, Spasovski, Vesna, Đorđević, Maja, Pavlović, Sonja, Stojiljković, Maja, "WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib" in 5th Belgrade Bioinformatics Conference (2024):72-72, https://hdl.handle.net/21.15107/rcub_imagine_2457 .