Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%–90% of ALS cases are spor...
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Frontiers Media S.A.
2025-07-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10593/full |
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| author | Eleonora Sabetta Karin Rallmann Jonas Bergquist Pille Taba Pille Taba Abigail L. Pfaff Abigail L. Pfaff Bal Hari Poudel Davide Ferrari Massimo Locatelli Sulev Kõks Sulev Kõks |
| author_facet | Eleonora Sabetta Karin Rallmann Jonas Bergquist Pille Taba Pille Taba Abigail L. Pfaff Abigail L. Pfaff Bal Hari Poudel Davide Ferrari Massimo Locatelli Sulev Kõks Sulev Kõks |
| author_sort | Eleonora Sabetta |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%–90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions. |
| format | Article |
| id | doaj-art-1a91ef635b804e17b5dbb7b4c69b3fd3 |
| institution | DOAJ |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Experimental Biology and Medicine |
| spelling | doaj-art-1a91ef635b804e17b5dbb7b4c69b3fd32025-08-20T03:13:21ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-07-0125010.3389/ebm.2025.1059310593Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencingEleonora Sabetta0Karin Rallmann1Jonas Bergquist2Pille Taba3Pille Taba4Abigail L. Pfaff5Abigail L. Pfaff6Bal Hari Poudel7Davide Ferrari8Massimo Locatelli9Sulev Kõks10Sulev Kõks11IRCCS Ospedale San Raffaele, Milan, ItalyDepartment of Neurology, Tartu University Hospital, Tartu, EstoniaAnalytical Chemistry and Neurochemistry, Department of Chemistry - Biomedical Center, Uppsala University, Uppsala, SwedenDepartment of Neurology, Tartu University Hospital, Tartu, EstoniaInstitute of Clinical Medicine, University Tartu, Tartu, EstoniaPerron Institute for Neurological and Translational Science, Perth, WA, AustraliaPersonalised Medicine Center, Murdoch University, Perth, WA, AustraliaPersonalised Medicine Center, Murdoch University, Perth, WA, AustraliaScienze Chimiche della Vita e della Sostenibilità Ambientale (SCVSA) Department, University of Parma, Parma, ItalyIRCCS Ospedale San Raffaele, Milan, ItalyPerron Institute for Neurological and Translational Science, Perth, WA, AustraliaPersonalised Medicine Center, Murdoch University, Perth, WA, AustraliaAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%–90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.https://www.ebm-journal.org/articles/10.3389/ebm.2025.10593/fullgenetic architecturesporadic amyotrophic lateral sclerosis (ALS)tandem repeatsneurodegenerative disordersshort-read sequencinglong-read sequencing |
| spellingShingle | Eleonora Sabetta Karin Rallmann Jonas Bergquist Pille Taba Pille Taba Abigail L. Pfaff Abigail L. Pfaff Bal Hari Poudel Davide Ferrari Massimo Locatelli Sulev Kõks Sulev Kõks Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing Experimental Biology and Medicine genetic architecture sporadic amyotrophic lateral sclerosis (ALS) tandem repeats neurodegenerative disorders short-read sequencing long-read sequencing |
| title | Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing |
| title_full | Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing |
| title_fullStr | Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing |
| title_full_unstemmed | Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing |
| title_short | Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing |
| title_sort | comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis advantages of long read vs short read sequencing |
| topic | genetic architecture sporadic amyotrophic lateral sclerosis (ALS) tandem repeats neurodegenerative disorders short-read sequencing long-read sequencing |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2025.10593/full |
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