@article{Mazzarotto:2026:10.1186/s13073-026-01749-0,
author = {Mazzarotto, F and Kalay, O and Arslan, E and Cinquina, V and Buchan, R and Bertini, V and Cavanagh, E and Turgut, D and Allouba, M and Afify, A and Halawa, S and Theotokis, P and Budak, G and Girolami, F and Azzu, A and Peldova, P and Matthews, N and Pennell, D and Bonaventura, J and Olivotto, I and Pelo, E and Colombi, M and Macek, M and Barton, P and Aguib, Y and Yacoub, M and Ritelli, M and Gennarelli, M and Tetikol, S and Walsh, R and Ware, J and Jain, A},
doi = {10.1186/s13073-026-01749-0},
journal = {Genome Medicine},
title = {Pangenomes aid accurate detection of large insertions and deletions from targeted sequencing: the case of cardiomyopathies},
url = {http://dx.doi.org/10.1186/s13073-026-01749-0},
volume = {18},
year = {2026}
}

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TY  - JOUR
AB  - BackgroundGene panels represent a widely used strategy for genetic testing in a vast range of Mendelian disorders. While this approach aids reliable bioinformatic detection of short coding variants, it often fails to detect many larger variants. Recent studies have recommended the adoption of pangenome references (as opposed to linear reference genomes like GRCh38) to augment detection of large variants from targeted sequencing, potentially providing diagnostic laboratories with the possibility to streamline diagnostic work-ups and reduce costs.MethodsHere, we analyze 1969 cardiomyopathy cases and 1805 controls sequenced with the Illumina Trusight Cardio panel using a pangenome-based workflow (GRAF) and five conventional orthogonal methodologies (GATK HaplotypeCaller, GATK-gCNV, ExomeDepth, Manta and Lumpy-SV) to detect variants ≥ 20 bp in size.ResultsFollowing lab-based variant validation by means of PCR and Sanger sequencing, we show that GRAF conjugates higher precision and recall (F1 score 0.86) compared with other methods (F1 0-0.57) in detecting potentially pathogenic variants ≥ 20 bp from short-read panel data. Results were complemented by a comparison of the tools’ performance in detecting ground truth variants on reference sample HG002 from Genome In A Bottle, which confirmed GRAF to outperform other tools also on exome sequencing (F1 0.97 vs. 0-0.94). Notably, in the HG002 benchmark dataset, GRAF also showed slightly improved performance compared to GATK HaplotypeCaller in the identification of small variants (1–19 bp; F1 0.975 vs. 0.968).ConclusionsOur results indicate that pangenome-based workflows aid improved detection of large variants from targeted sequencing data in the clinical context and suggest that they may contribute to more unified variant detection frameworks for all-size genetic variants in the future.
AU  - Mazzarotto,F
AU  - Kalay,O
AU  - Arslan,E
AU  - Cinquina,V
AU  - Buchan,R
AU  - Bertini,V
AU  - Cavanagh,E
AU  - Turgut,D
AU  - Allouba,M
AU  - Afify,A
AU  - Halawa,S
AU  - Theotokis,P
AU  - Budak,G
AU  - Girolami,F
AU  - Azzu,A
AU  - Peldova,P
AU  - Matthews,N
AU  - Pennell,D
AU  - Bonaventura,J
AU  - Olivotto,I
AU  - Pelo,E
AU  - Colombi,M
AU  - Macek,M
AU  - Barton,P
AU  - Aguib,Y
AU  - Yacoub,M
AU  - Ritelli,M
AU  - Gennarelli,M
AU  - Tetikol,S
AU  - Walsh,R
AU  - Ware,J
AU  - Jain,A
DO  - 10.1186/s13073-026-01749-0
PY  - 2026///
SN  - 1756-994X
TI  - Pangenomes aid accurate detection of large insertions and deletions from targeted sequencing: the case of cardiomyopathies
T2  - Genome Medicine
UR  - http://dx.doi.org/10.1186/s13073-026-01749-0
VL  - 18
ER  - 

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