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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort †

by
Zakhiriddin Khojakulov
1,
Robin J. Palvadeau
1,
Müge Kovancılar-Koç
1,
Irmak Atay
1,
Irmak Şahbaz
1,
Şeyma Tekgül
1,
Ayça Şahin
1,
Esmer Zeynep Duru Badakal
1,
Tuğçe Gül-Demirkale
1,
Vildan Çiftçi
1,
Elif Bayraktar
1,
Ceren Tunca
1,
Natalia Smolina
1,
Fulya Akçimen
2 and
Ayşe Nazlı Başak
1,*
1
Neurodegeneration Research Laboratory (NDAL), Research Center for Translational Medicine (KUTTAM), School of Medicine, Koç University, 34010 Istanbul, Turkey
2
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
†
This study is dedicated to the memory of Mrs. Suna Kıraç on the 20th anniversary of NDAL.
Int. J. Mol. Sci. 2026, 27(10), 4345; https://doi.org/10.3390/ijms27104345
Submission received: 5 March 2026 / Revised: 4 April 2026 / Accepted: 9 April 2026 / Published: 13 May 2026
(This article belongs to the Section Molecular Genetics and Genomics)
Review Reports Versions Notes

Abstract

Short tandem repeat (STR) expansions are a major cause of neurodegenerative disorders; however, their genetic and clinical heterogeneity complicates diagnosis. STR detection remains limited in routine short-read next-generation sequencing (NGS) workflows. We evaluated the diagnostic yield and clinical utility of computational STR genotyping in a large Turkish neurodegenerative disease cohort. ExpansionHunter was applied to NGS data from 3150 patients and 146 controls, targeting 15 disease-associated STR loci. To improve genotyping of poorly captured exonic regions in exome data, the default locus coverage threshold was reduced from 10× to 3×. Candidate expansions were visually inspected using REViewer and validated by conventional molecular methods. Computational analysis detected 28 pathogenic and 160 intermediate expansions. Of these, 23 were confirmed as pathogenic, and eight initially classified as intermediate were reclassified as pathogenic after conventional validation, resulting in 31 pathogenic cases across 28 families: HTT (n = 8), ATXN2 (n = 5), ATXN1 (n = 4), DMPK (n = 3), PABPN1 (n = 3), TBP (n = 2), and single cases in AR, ATN1, and CACNA1A. Lowering the coverage threshold markedly increased genotyping rates at low-coverage loci in exome data, particularly in ATXN2. Genetic findings were largely consistent with clinical pre-diagnosis and the additional diagnostic yield was 0.95%. These findings support integrating STR analysis into routine neurogenetic diagnostics.
Keywords: neurodegenerative diseases; computational genotyping; ExpansionHunter; short tandem repeats; STR; NGS neurodegenerative diseases; computational genotyping; ExpansionHunter; short tandem repeats; STR; NGS

Share and Cite

MDPI and ACS Style

Khojakulov, Z.; J. Palvadeau, R.; Kovancılar-Koç, M.; Atay, I.; Şahbaz, I.; Tekgül, Ş.; Şahin, A.; Duru Badakal, E.Z.; Gül-Demirkale, T.; Çiftçi, V.; et al. Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort. Int. J. Mol. Sci. 2026, 27, 4345. https://doi.org/10.3390/ijms27104345

AMA Style

Khojakulov Z, J. Palvadeau R, Kovancılar-Koç M, Atay I, Şahbaz I, Tekgül Ş, Şahin A, Duru Badakal EZ, Gül-Demirkale T, Çiftçi V, et al. Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort. International Journal of Molecular Sciences. 2026; 27(10):4345. https://doi.org/10.3390/ijms27104345

Chicago/Turabian Style

Khojakulov, Zakhiriddin, Robin J. Palvadeau, Müge Kovancılar-Koç, Irmak Atay, Irmak Şahbaz, Şeyma Tekgül, Ayça Şahin, Esmer Zeynep Duru Badakal, Tuğçe Gül-Demirkale, Vildan Çiftçi, and et al. 2026. "Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort" International Journal of Molecular Sciences 27, no. 10: 4345. https://doi.org/10.3390/ijms27104345

APA Style

Khojakulov, Z., J. Palvadeau, R., Kovancılar-Koç, M., Atay, I., Şahbaz, I., Tekgül, Ş., Şahin, A., Duru Badakal, E. Z., Gül-Demirkale, T., Çiftçi, V., Bayraktar, E., Tunca, C., Smolina, N., Akçimen, F., & Başak, A. N. (2026). Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort. International Journal of Molecular Sciences, 27(10), 4345. https://doi.org/10.3390/ijms27104345

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