Whole-exome sequencing identifies a missense variant in the cytoskeletal gene SVIL implicating actin remodeling in COVID-19 severity in a Pakistani cohort
5 affiliations
- 1Department of Anatomy, Ziauddin University, Karachi, Pakistan
- 2College of Molecular Medicine & Research Department, Faculty of Health Sciences, Ziauddin University, Karachi, Pakistan
- 3Department of Pulmonology, Ziauddin Hospital, Karachi, Pakistan
- 4Department of Medicine, Ziauddin Hospital, Karachi, Pakistan
- 5Department of Research, Faculty of Health Sciences, Ziauddin University, Karachi, Pakistan
Abstract
Background: The current study investigated host genetic associations with disease severity in COVID-19 patients of South Asian origin and explored its molecular basis. Methods: Covid-19 patients were stratified into disease severity groups based on the clinical and radiographic findings. Genomic DNA was extracted from peripheral blood samples. A two-step discovery and validation approach was utilized for genetic analysis. Whole-exome sequencing (WES) based variant prioritization was performed in a discovery cohort of severe disease patients followed by validation in an independent cohort. Bioinformatics analysis including data alignment, and annotation to the GRCh38 human reference genome was done by Ensembl VEP software. WES filtration pipeline utilizing predicted pathogenicity and population allele frequencies focused on the low-frequency and rare variants to filter out the variants of concern. Computational predictive tools and simulations were utilized for the structural and functional analysis of the identified high-risk SNP. Statistical analyses were done by SPSS version 24 and GraphPad Prism version 10. Results: The missense variant rs199726033 of SVIL gene demonstrated the highest recurrence in the WES discovery cohort. The minor allele frequency (29.2%) was substantially higher than that reported for South Asians in the gnomAD v4 database (1.051%). A significant association of the mutant AC genotype of rs199726033 and disease severity was found in the validation cohort. Protein modeling and structural analysis localized the variant within a functionally conserved Gelsolin domain. Moreover, functional and pathway analysis of the SVIL variant indicates its potential role in actin filament remodeling relevant to COVID-19 related vasculopathy and cytoskeleton dynamics thus influencing host-viral interactions. Conclusion: A SVIL missense variant is associated with disease severity and may influence host cytoskeletal processes relevant to COVID-19 severity.
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BibTeX
@article{sadiq2026wholeexome,
title = {{Whole-exome sequencing identifies a missense variant in the cytoskeletal gene SVIL implicating actin remodeling in COVID-19 severity in a Pakistani cohort}},
author = {Madeeha Sadiq and Bushra Wasim and Ambrina Khatoon and Ashok Kumar and Nida Hussain and Urfa Tabassum Kayani and Talat Mirza},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0360429},
url = {https://doi.org/10.1371/journal.pone.0360429},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Whole-exome sequencing identifies a missense variant in the cytoskeletal gene SVIL implicating actin remodeling in COVID-19 severity in a Pakistani cohort
AU - Madeeha Sadiq
AU - Bushra Wasim
AU - Ambrina Khatoon
AU - Ashok Kumar
AU - Nida Hussain
AU - Urfa Tabassum Kayani
AU - Talat Mirza
PY - 2026
DA - 2026/10/12
JO - PLOS One
DO - 10.1371/journal.pone.0360429
UR - https://doi.org/10.1371/journal.pone.0360429
AB - Background: The current study investigated host genetic associations with disease severity in COVID-19 patients of South Asian origin and explored its molecular basis. Methods: Covid-19 patients were stratified into disease severity groups based on the clinical and radiographic findings. Genomic DNA was extracted from peripheral blood samples. A two-step discovery and validation approach was utilized for genetic analysis. Whole-exome sequencing (WES) based variant prioritization was performed in a discovery cohort of severe disease patients followed by validation in an independent cohort. Bioinformatics analysis including data alignment, and annotation to the GRCh38 human reference genome was done by Ensembl VEP software. WES filtration pipeline utilizing predicted pathogenicity and population allele frequencies focused on the low-frequency and rare variants to filter out the variants of concern. Computational predictive tools and simulations were utilized for the structural and functional analysis of the identified high-risk SNP. Statistical analyses were done by SPSS version 24 and GraphPad Prism version 10. Results: The missense variant rs199726033 of SVIL gene demonstrated the highest recurrence in the WES discovery cohort. The minor allele frequency (29.2%) was substantially higher than that reported for South Asians in the gnomAD v4 database (1.051%). A significant association of the mutant AC genotype of rs199726033 and disease severity was found in the validation cohort. Protein modeling and structural analysis localized the variant within a functionally conserved Gelsolin domain. Moreover, functional and pathway analysis of the SVIL variant indicates its potential role in actin filament remodeling relevant to COVID-19 related vasculopathy and cytoskeleton dynamics thus influencing host-viral interactions. Conclusion: A SVIL missense variant is associated with disease severity and may influence host cytoskeletal processes relevant to COVID-19 severity.
SN - 1932-6203
ER -