Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease
Аутори
Mitić, Martina MiaUšjak, Dušan
Milošević, Maja
Cumbo, Marija
Dunjić Manevski, Sofija
Tomić, Branko
Petrović, Ivana
Otašević, Petar
Micović, Slobodan
Bojić, Milovan
Đorđević, Valentina
Остала ауторства
Morić, IvanaĐorđević, Valentina
Конференцијски прилог (Објављена верзија)
,
© 2023 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
Метаподаци
Приказ свих података о документуАпстракт
Normal aortic valve consists of three cusps that develop in the embryonic stage. Unicuspid
aortic valve (UAV) is a rare congenital anomaly resulting in only one cusp with estimated
prevalence of 0.02% in general population. Aim of this study was to identify genetic
variants possibly associated with development of UAV. The study included 17 subjects,
namely 5 UAV patients and their healthy family members without UAV disorder. Total
DNA was isolated from venous blood samples and whole exomes sequencing (WES) was
performed using BGI’s WES protocol. Adapter-trimmed and quality-filtered reads (fastp)
were mapped to hg38 reference genome using BWA/SAMtools. VCF files were generated
using GATK (BaseRecalibrator, HaplotypeCaller) and annotated with InterVar and AnnoVar
tools. Rare heterozygous variants present in UAV patients were found in NOTCH1, TGFB2,
MYH6, EGFR, FBN2, C1R, ROBO4 and TBX5, genes associated with development of aortic
valves. Among these, most were missense mutatio...ns with damaging effects as predicted
using in silico tools (SIFT and/or Polyphen). Only mutation in MYH6 p.Ala1130Ser was
found in at least two different UAV patients. Also, rare homozygous missense mutation
p.Gly577Ser with high damaging potential was found in ADAMTS5 gene. Besides, highly
damaging heterozygous missense mutations were detected in gene interacting functional
partners (STRING) of genes associated with development of aortic valves: DVL1, THBS1,
NOTCH4, ADAMTS3, FBN1, NOTCH2, ADAM17, LRP5, WWTR1, C1S, ANKRD6 and TNNI1,
as well as homozygous in ACAN and KNG1. Taken together, malfunctions in ADAMTS5,
ACTA2, MYH6, FBN2, AXIN1, CELSR1 or TBX5 networks were found to be common in at
least two UAV patients, suggesting existence of genetic basis in UAV disorder, possibly as
a result of combined effects of multiple variants.
Кључне речи:
unicuspid aortic valve / congenital heart disease / whole exome sequencing / genetic variants / valvesИзвор:
4th Belgrade Bioinformatics Conference, 2023, 4, 59-59Издавач:
- Belgrade : Institute of molecular genetics and genetic engineering
Напомена:
- Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 2023
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Mitić, Martina Mia AU - Ušjak, Dušan AU - Milošević, Maja AU - Cumbo, Marija AU - Dunjić Manevski, Sofija AU - Tomić, Branko AU - Petrović, Ivana AU - Otašević, Petar AU - Micović, Slobodan AU - Bojić, Milovan AU - Đorđević, Valentina PY - 2023 UR - https://belbi.bg.ac.rs/ UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1999 AB - Normal aortic valve consists of three cusps that develop in the embryonic stage. Unicuspid aortic valve (UAV) is a rare congenital anomaly resulting in only one cusp with estimated prevalence of 0.02% in general population. Aim of this study was to identify genetic variants possibly associated with development of UAV. The study included 17 subjects, namely 5 UAV patients and their healthy family members without UAV disorder. Total DNA was isolated from venous blood samples and whole exomes sequencing (WES) was performed using BGI’s WES protocol. Adapter-trimmed and quality-filtered reads (fastp) were mapped to hg38 reference genome using BWA/SAMtools. VCF files were generated using GATK (BaseRecalibrator, HaplotypeCaller) and annotated with InterVar and AnnoVar tools. Rare heterozygous variants present in UAV patients were found in NOTCH1, TGFB2, MYH6, EGFR, FBN2, C1R, ROBO4 and TBX5, genes associated with development of aortic valves. Among these, most were missense mutations with damaging effects as predicted using in silico tools (SIFT and/or Polyphen). Only mutation in MYH6 p.Ala1130Ser was found in at least two different UAV patients. Also, rare homozygous missense mutation p.Gly577Ser with high damaging potential was found in ADAMTS5 gene. Besides, highly damaging heterozygous missense mutations were detected in gene interacting functional partners (STRING) of genes associated with development of aortic valves: DVL1, THBS1, NOTCH4, ADAMTS3, FBN1, NOTCH2, ADAM17, LRP5, WWTR1, C1S, ANKRD6 and TNNI1, as well as homozygous in ACAN and KNG1. Taken together, malfunctions in ADAMTS5, ACTA2, MYH6, FBN2, AXIN1, CELSR1 or TBX5 networks were found to be common in at least two UAV patients, suggesting existence of genetic basis in UAV disorder, possibly as a result of combined effects of multiple variants. PB - Belgrade : Institute of molecular genetics and genetic engineering C3 - 4th Belgrade Bioinformatics Conference T1 - Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease EP - 59 SP - 59 VL - 4 UR - https://hdl.handle.net/21.15107/rcub_imagine_1999 ER -
@conference{ author = "Mitić, Martina Mia and Ušjak, Dušan and Milošević, Maja and Cumbo, Marija and Dunjić Manevski, Sofija and Tomić, Branko and Petrović, Ivana and Otašević, Petar and Micović, Slobodan and Bojić, Milovan and Đorđević, Valentina", year = "2023", abstract = "Normal aortic valve consists of three cusps that develop in the embryonic stage. Unicuspid aortic valve (UAV) is a rare congenital anomaly resulting in only one cusp with estimated prevalence of 0.02% in general population. Aim of this study was to identify genetic variants possibly associated with development of UAV. The study included 17 subjects, namely 5 UAV patients and their healthy family members without UAV disorder. Total DNA was isolated from venous blood samples and whole exomes sequencing (WES) was performed using BGI’s WES protocol. Adapter-trimmed and quality-filtered reads (fastp) were mapped to hg38 reference genome using BWA/SAMtools. VCF files were generated using GATK (BaseRecalibrator, HaplotypeCaller) and annotated with InterVar and AnnoVar tools. Rare heterozygous variants present in UAV patients were found in NOTCH1, TGFB2, MYH6, EGFR, FBN2, C1R, ROBO4 and TBX5, genes associated with development of aortic valves. Among these, most were missense mutations with damaging effects as predicted using in silico tools (SIFT and/or Polyphen). Only mutation in MYH6 p.Ala1130Ser was found in at least two different UAV patients. Also, rare homozygous missense mutation p.Gly577Ser with high damaging potential was found in ADAMTS5 gene. Besides, highly damaging heterozygous missense mutations were detected in gene interacting functional partners (STRING) of genes associated with development of aortic valves: DVL1, THBS1, NOTCH4, ADAMTS3, FBN1, NOTCH2, ADAM17, LRP5, WWTR1, C1S, ANKRD6 and TNNI1, as well as homozygous in ACAN and KNG1. Taken together, malfunctions in ADAMTS5, ACTA2, MYH6, FBN2, AXIN1, CELSR1 or TBX5 networks were found to be common in at least two UAV patients, suggesting existence of genetic basis in UAV disorder, possibly as a result of combined effects of multiple variants.", publisher = "Belgrade : Institute of molecular genetics and genetic engineering", journal = "4th Belgrade Bioinformatics Conference", title = "Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease", pages = "59-59", volume = "4", url = "https://hdl.handle.net/21.15107/rcub_imagine_1999" }
Mitić, M. M., Ušjak, D., Milošević, M., Cumbo, M., Dunjić Manevski, S., Tomić, B., Petrović, I., Otašević, P., Micović, S., Bojić, M.,& Đorđević, V.. (2023). Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease. in 4th Belgrade Bioinformatics Conference Belgrade : Institute of molecular genetics and genetic engineering., 4, 59-59. https://hdl.handle.net/21.15107/rcub_imagine_1999
Mitić MM, Ušjak D, Milošević M, Cumbo M, Dunjić Manevski S, Tomić B, Petrović I, Otašević P, Micović S, Bojić M, Đorđević V. Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease. in 4th Belgrade Bioinformatics Conference. 2023;4:59-59. https://hdl.handle.net/21.15107/rcub_imagine_1999 .
Mitić, Martina Mia, Ušjak, Dušan, Milošević, Maja, Cumbo, Marija, Dunjić Manevski, Sofija, Tomić, Branko, Petrović, Ivana, Otašević, Petar, Micović, Slobodan, Bojić, Milovan, Đorđević, Valentina, "Using whole exome sequencing to explore genetic basis of unicuspid aortic valve disease" in 4th Belgrade Bioinformatics Conference, 4 (2023):59-59, https://hdl.handle.net/21.15107/rcub_imagine_1999 .