TY  - 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 .