Accurate repeat expansion genotyping from whole-genome and real-time targeted nanopore sequencing with Mahi-mahi
- 1University of Washington
Abstract
Tandem repeat expansions cause more than 60 Mendelian disorders but are difficult to detect and size accurately with short-read sequencing because of their length and repetitive structure. Long-read sequencing (LRS) resolves these loci directly, yet analytic tooling for nanopore sequencing data has lagged behind that available for other long-read platforms. Here we present Mahi-mahi, a tandem repeat genotyper designed for nanopore reads that reports allele-level repeat length, motif composition, interruptions, and read-level flags for systematic basecalling artifacts. Across six Genome in a Bottle samples, whole-genome and adaptive sampling (real-time targeted) data returned calls within one repeat unit of each other for 829 of 832 alleles, and Mahi-mahi calls were within one repeat unit of orthogonal HiFi data at 95.6% of compared alleles after excluding three loci at which the two tools define the repeat differently. In 245 samples from the 1000 Genomes Project, Mahi-mahi calls were within one repeat unit of assembly-derived calls for 98.6% of 10,927 alleles at 57 loci, and Mahi-mahi distinguished pathogenic from nonpathogenic RFC1 alleles of overlapping size by motif. Across 14 Coriell reference lines, Mahi-mahi identified the expected expansion in every line and agreed with orthogonal assays to within two repeat units at HTT, ATXN1, DMPK, and PABPN1. Finally, in 103 samples from three laboratories, Mahi-mahi detected an expanded allele in all samples in which prior testing had reported a pathogenic expansion, assigned the same category as the referring laboratory for 98% of 180 genotypes, and identified known ATXN1 interruption structure. Our results demonstrate that Mahi-mahi accurately identifies repeat expansions at disease-associated loci and could serve as a single assay to evaluate repeat expansions.
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BibTeX
@misc{gibson2026accurate,
title = {{Accurate repeat expansion genotyping from whole-genome and real-time targeted nanopore sequencing with Mahi-mahi}},
author = {S. B. Gibson and R. N. Palmer and S. Hollizeck and W. Koole and H. M. Jeffery and M. Albring and J. G. Buchan and R. K. Cheetham and M. G. Elferink and J. Goffena and E. J. Hamlin and R. Jansen and P. J. Lockhart and R. Martin and A. L. Miller and I. van Outersterp and T. Prall and J. Rosinski and S. M. Rowley and S. Sadedin and D. Sewell and M. Todd and A. Zabelkin and M. P. G. Zalusky and B. van der Zwaag and S. Nurk and S. Juul and K. L. I. van Gassen and S. Lunke and D. E. Miller and P. Rescheneder},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.26365781},
url = {https://www.medrxiv.org/content/10.64898/2026.10.16.26365781v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Accurate repeat expansion genotyping from whole-genome and real-time targeted nanopore sequencing with Mahi-mahi
AU - S. B. Gibson
AU - R. N. Palmer
AU - S. Hollizeck
AU - W. Koole
AU - H. M. Jeffery
AU - M. Albring
AU - J. G. Buchan
AU - R. K. Cheetham
AU - M. G. Elferink
AU - J. Goffena
AU - E. J. Hamlin
AU - R. Jansen
AU - P. J. Lockhart
AU - R. Martin
AU - A. L. Miller
AU - I. van Outersterp
AU - T. Prall
AU - J. Rosinski
AU - S. M. Rowley
AU - S. Sadedin
AU - D. Sewell
AU - M. Todd
AU - A. Zabelkin
AU - M. P. G. Zalusky
AU - B. van der Zwaag
AU - S. Nurk
AU - S. Juul
AU - K. L. I. van Gassen
AU - S. Lunke
AU - D. E. Miller
AU - P. Rescheneder
PY - 2026
DA - 2026/10/16
PB - medRxiv
DO - 10.64898/2026.10.16.26365781
UR - https://www.medrxiv.org/content/10.64898/2026.10.16.26365781v1
AB - Tandem repeat expansions cause more than 60 Mendelian disorders but are difficult to detect and size accurately with short-read sequencing because of their length and repetitive structure. Long-read sequencing (LRS) resolves these loci directly, yet analytic tooling for nanopore sequencing data has lagged behind that available for other long-read platforms. Here we present Mahi-mahi, a tandem repeat genotyper designed for nanopore reads that reports allele-level repeat length, motif composition, interruptions, and read-level flags for systematic basecalling artifacts. Across six Genome in a Bottle samples, whole-genome and adaptive sampling (real-time targeted) data returned calls within one repeat unit of each other for 829 of 832 alleles, and Mahi-mahi calls were within one repeat unit of orthogonal HiFi data at 95.6% of compared alleles after excluding three loci at which the two tools define the repeat differently. In 245 samples from the 1000 Genomes Project, Mahi-mahi calls were within one repeat unit of assembly-derived calls for 98.6% of 10,927 alleles at 57 loci, and Mahi-mahi distinguished pathogenic from nonpathogenic RFC1 alleles of overlapping size by motif. Across 14 Coriell reference lines, Mahi-mahi identified the expected expansion in every line and agreed with orthogonal assays to within two repeat units at HTT, ATXN1, DMPK, and PABPN1. Finally, in 103 samples from three laboratories, Mahi-mahi detected an expanded allele in all samples in which prior testing had reported a pathogenic expansion, assigned the same category as the referring laboratory for 98% of 180 genotypes, and identified known ATXN1 interruption structure. Our results demonstrate that Mahi-mahi accurately identifies repeat expansions at disease-associated loci and could serve as a single assay to evaluate repeat expansions.
ER -