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Article

Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study

by
Faisal E. Ibrahim
1,2,3,†,
BalaSubramani Gattu Linga
1,2,†,
Muthanna Samara
4,
Jameela Roshanuddin
1,2,5,
Salma Younes
6,7,
Gheyath Nasrallah
6,7,
Hatem Zayed
6,
M. Walid Qoronfleh
8,*,
Sawsan G. A. A. Mohammed
9,
Dalia El Khoury
10,
Dinesh Velayutham
11,
Ghassan Abdoh
12,
Hilal Al Rifai
13 and
Nader Al-Dewik
1,2,3,5,12,13,14,*
1
Department of Research, Women’s Wellness and Research Center, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha 0974, Qatar
2
Translational and Precision Medicine Research, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha 0974, Qatar
3
Translational Research Institute (TRI), Hamad Medical Corporation (HMC), Doha 3050, Qatar
4
Department of Psychology, Kingston University London, Penrhyn Road, London KT1 2EE, UK
5
Qatar Preterm and Precision Medicine Research Clinic, Women’s Wellness and Research Center, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha 0974, Qatar
6
Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha 2713, Qatar
7
Biomedical Research Center, QU Health, Qatar University, Doha 2713, Qatar
8
Healthcare Research & Policy Division, Q3 Research Institute (QRI), Ann Arbor, MI 48197, USA
9
QU Health, College of Medicine, Qatar University, Doha 2713, Qatar
10
Department of Family Relations and Applied Nutrition, University of Guelph, 50 Stone Road East, Guelph, ON N1G2W1, Canada
11
Liberal Arts and Science (LAS), Hamad Bin Khalifa University (HBKU), P.O. Box 34110, Doha 34110, Qatar
12
Department of Neonatology, Neonatal Intensive Care Unit (NICU), Newborn Screening Unit, Women’s Wellness and Research Center (WWRC), Hamad Medical Corporation (HMC), Doha 3050, Qatar
13
Genomics and Precision Medicine (GPM), College of Health & Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha 34110, Qatar
14
Faculty of Health and Social Care Sciences, Kingston University, St. George’s University of London, London KT1 2EE, UK
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2025, 13(9), 2210; https://doi.org/10.3390/biomedicines13092210
Submission received: 21 May 2025 / Revised: 4 August 2025 / Accepted: 6 August 2025 / Published: 9 September 2025
(This article belongs to the Special Issue The Human Proteinomics in Disease, Diagnostics and Translation into Precision Medicine: Current Status and Future Prospects—2nd Edition)
Versions Notes

Abstract

Background: Biotinidase deficiency (BD) is a common autosomal recessive metabolic disorder in Qatar and the Arab world. It is treatable if detected early, making it essential to understand the genetic variants involved. This study aimed to investigate the carrier frequency of BD-related variants in a healthy Qatari population, reflecting the genetic landscape of the broader Middle Eastern region; classify them using bioinformatics tools; and compare findings with global datasets. Methods: Whole-genome sequencing data from 14,669 participants in the Qatar Genome Program (QGP), a multiethnic cohort including Qatari nationals and long-term residents (≥15 years), were analyzed to identify BTD variants. A total of 723, including 653 single-nucleotide polymorphisms (SNPs) and 70 structural variants (SVs) in BTD associated with BD, were screened against the Qatari cohort and compared with international data. In silico tools were used to assess variant pathogenicity, conservation, and protein stability. Molecular dynamics (MD) simulations were performed to evaluate structural and functional changes in the BTD. Results: A total of 80 SNPs and 3 SVs were identified, among which 21 variants (19 SNPs and 2 SVs) were classified as pathogenic or likely pathogenic, according to ClinVar. The carrier frequency of BTD-related variants in Qatar was 1:20, primarily driven by rs13078881 (D444H). Molecular dynamics (MD) simulations revealed significant conformational changes with H323R, D444H, and P497S, which demonstrated increased flexibility (higher RMSD/RMSF and PCA trace values). Additionally, R209C and D444H showed reduced compactness (higher Rg) and distinct energy minima, suggesting altered conformational states. Conclusions: This study demonstrates a high carrier frequency of pathogenic BTD variants in the Qatari population, underscoring the need to integrate these SNPs and SVs into the national genomic neonatal screening program (gNBS) for enhanced early detection and treatment strategies. The mild structural deviations observed in the D444H mutant through MD simulations may explain its association with milder clinical phenotypes of BTD, offering valuable insights for personalized therapeutic approaches.
Keywords: biotinidase deficiency; genotype–phenotype correlation; Qatar Genome Program; single-nucleotide polymorphism; protein stability; molecular dynamics biotinidase deficiency; genotype–phenotype correlation; Qatar Genome Program; single-nucleotide polymorphism; protein stability; molecular dynamics

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MDPI and ACS Style

Ibrahim, F.E.; Gattu Linga, B.; Samara, M.; Roshanuddin, J.; Younes, S.; Nasrallah, G.; Zayed, H.; Qoronfleh, M.W.; Mohammed, S.G.A.A.; El Khoury, D.; et al. Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study. Biomedicines 2025, 13, 2210. https://doi.org/10.3390/biomedicines13092210

AMA Style

Ibrahim FE, Gattu Linga B, Samara M, Roshanuddin J, Younes S, Nasrallah G, Zayed H, Qoronfleh MW, Mohammed SGAA, El Khoury D, et al. Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study. Biomedicines. 2025; 13(9):2210. https://doi.org/10.3390/biomedicines13092210

Chicago/Turabian Style

Ibrahim, Faisal E., BalaSubramani Gattu Linga, Muthanna Samara, Jameela Roshanuddin, Salma Younes, Gheyath Nasrallah, Hatem Zayed, M. Walid Qoronfleh, Sawsan G. A. A. Mohammed, Dalia El Khoury, and et al. 2025. "Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study" Biomedicines 13, no. 9: 2210. https://doi.org/10.3390/biomedicines13092210

APA Style

Ibrahim, F. E., Gattu Linga, B., Samara, M., Roshanuddin, J., Younes, S., Nasrallah, G., Zayed, H., Qoronfleh, M. W., Mohammed, S. G. A. A., El Khoury, D., Velayutham, D., Abdoh, G., Al Rifai, H., & Al-Dewik, N. (2025). Genomic and Structural Investigation of Mutations in Biotinidase (BTD) Gene Deficiency in Greater Middle Eastern Cohort: Insights from Molecular Dynamics Study. Biomedicines, 13(9), 2210. https://doi.org/10.3390/biomedicines13092210

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