Genomic Landscape And Structural Impact Of Biotinidase (BTD) Variants In A Middle Eastern Population
<h3 dir="ltr">Background</h3><p dir="ltr">Biotinidase deficiency (BD) is an autosomal recessive metabolic disorder that is fully treatable if diagnosed early. The condition is relatively common in the Middle Eastern region, highlighting the importance of underst...
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2025
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| Summary: | <h3 dir="ltr">Background</h3><p dir="ltr">Biotinidase deficiency (BD) is an autosomal recessive metabolic disorder that is fully treatable if diagnosed early. The condition is relatively common in the Middle Eastern region, highlighting the importance of understanding population-specific pathogenic variants. This study investigated the frequency, clinical relevance, and structural effects of <i>BTD</i> gene variants within the Qatar Genome Program (QGP) cohort to inform precision screening strategies. </p><h3 dir="ltr">Methods</h3><p dir="ltr">Whole-genome sequencing data from 14,669 QGP participants were examined to identify single-nucleotide and structural variants in <i>BTD</i>. Variant frequencies were compared with global population databases. In silico pathogenicity prediction, conservation analysis, and protein stability assessments were performed. Molecular dynamics (MD) simulations were employed to assess the structural perturbations associated with selected missense variants. </p><h3 dir="ltr">Results</h3><p dir="ltr">We identified 80 <i>BTD</i> SNPs and 3 structural variants in the cohort. Of these, 21 variants (19 SNPs; 2 SVs) were classified as pathogenic or likely pathogenic. The overall carrier frequency of BD-associated variants in Qatar was approximately 1 in 20, primarily driven by the recurrent QULSS2025 variant D444H. MD simulations indicated that H323R, D444H, and P497S exhibited greater structural flexibility (increased RMSD/RMSF and PCA trace values), whereas R209C and D444H demonstrated reduced compactness (higher radius of gyration). D444H exhibited subtle yet consistent structural rearrangements, consistent with its known presentation as a milder clinical phenotype. </p><h3 dir="ltr">Conclusion</h3><p dir="ltr">The high carrier frequency of <i>BTD</i> pathogenic variants in Qatar supports the inclusion of these alleles in national genomic newborn screening programs. Structural insights from MD simulations, particularly for D444H, provide mechanistic evidence for phenotype variability and highlight opportunities for genotype-guided clinical management and early intervention strategies.</p><h2 dir="ltr">Other Information</h2><p dir="ltr">Conference information: 18th Edition of the Qatar University Life Sciences Symposium Bio-Environment: Advances and Innovations. (26 - 27 Nov 2025, Qatar University, Doha - Qatar)<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" rel="noreferrer noopener" target="_blank">https://creativecommons.org/licenses/by/4.0/</a></p><p dir="ltr">See the conference information on the organizer's website: <a href="https://www.qu.edu.qa/en-us/conference/QULSS2025/Pages/default.aspx" rel="noreferrer noopener" target="_blank">https://www.qu.edu.qa/en-us/conference/QULSS2025/Pages/default.aspx</a></p> |
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