Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients
4 affiliations
- 1Hong Kong Genome Institute, Hong Kong Special Administrative Region
- 2Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
- 3Department of Clinical Genetics, Hong Kong Children’s Hospital
- 4Division of Neurology, Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong
Abstract
Genetic neurological disorders are highly heterogeneous, and many are driven by complex variants that challenge short‑read genome sequencing (srGS). Long‑read genome sequencing (lrGS) has recently shown promise, but head‑to‑head evaluations are limited. A direct comparison study of srGS and lrGS was performed for 310 families with undiagnosed neurological disorders from the Hong Kong Genome Project to assess their diagnostic performance, technical capabilities and costing. Genome sequencing showed an overall diagnostic yield of 22.6% (n = 70/310, 77 variants). lrGS and srGS showed comparable variant detection rates at 92.2% (n = 71/77) and 96.1% (n = 74/77), respectively. lrGS solely confirmed three repeat expansions with phased methylation data and enhanced accuracy in two complex structural variants. srGS detected six variants in homopolymeric regions that were missed by lrGS. Costing analysis revealed a comparable unit cost per sample for srGS and lrGS with USD1,545.97 and USD1,580.00, respectively. This study demonstrated that srGS excels in detecting variants near homopolymers while lrGS offers better resolution for complex variants and enables the simultaneous analysis of methylation and phasing. Although lrGS is not yet capable of fully replacing srGS, we anticipate that the continued technical improvement would position lrGS as the first‑tier genomic test for neurological disorders.
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BibTeX
@article{chan2026systematic,
title = {{Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients}},
author = {Dream Lok Sze Chan and Helen Ying Fung Tam and Amy Hin Yan Tong and Wei Ma and Chak Sing Lau and Ho Ming Luk and Shirley Yin Yu Pang and Shirley Sze Wing Cheng and Yuan Gao and Lai Ting Leung and Denis Long Him Yeung and Claudia Ching Yan Chung and Steve Tsz Fung Chan and Shirley Pik Ying Hue and Anson Man Chun Xi and Dicky Or and Steve Cheuk Yiu Yeung and Jamie Sui Lam Kwok and Nattily Sum Yin Tai and Carol Ching Fun Lau and Wai Lap Wong and Raven Yan Wah Lee and Janice Kai Ning Wong and Hong Kong Genome Project and Annie Tsz Wai Chu and Brian Hon Yin Chung},
journal = {npj Genomic Medicine},
year = {2026},
month = jun,
doi = {10.1038/s41525-026-00593-w},
url = {https://doi.org/10.1038/s41525-026-00593-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients
AU - Dream Lok Sze Chan
AU - Helen Ying Fung Tam
AU - Amy Hin Yan Tong
AU - Wei Ma
AU - Chak Sing Lau
AU - Ho Ming Luk
AU - Shirley Yin Yu Pang
AU - Shirley Sze Wing Cheng
AU - Yuan Gao
AU - Lai Ting Leung
AU - Denis Long Him Yeung
AU - Claudia Ching Yan Chung
AU - Steve Tsz Fung Chan
AU - Shirley Pik Ying Hue
AU - Anson Man Chun Xi
AU - Dicky Or
AU - Steve Cheuk Yiu Yeung
AU - Jamie Sui Lam Kwok
AU - Nattily Sum Yin Tai
AU - Carol Ching Fun Lau
AU - Wai Lap Wong
AU - Raven Yan Wah Lee
AU - Janice Kai Ning Wong
AU - Hong Kong Genome Project
AU - Annie Tsz Wai Chu
AU - Brian Hon Yin Chung
PY - 2026
DA - 2026/06/01
JO - npj Genomic Medicine
DO - 10.1038/s41525-026-00593-w
UR - https://doi.org/10.1038/s41525-026-00593-w
AB - Genetic neurological disorders are highly heterogeneous, and many are driven by complex variants that challenge short‑read genome sequencing (srGS). Long‑read genome sequencing (lrGS) has recently shown promise, but head‑to‑head evaluations are limited. A direct comparison study of srGS and lrGS was performed for 310 families with undiagnosed neurological disorders from the Hong Kong Genome Project to assess their diagnostic performance, technical capabilities and costing. Genome sequencing showed an overall diagnostic yield of 22.6% (n = 70/310, 77 variants). lrGS and srGS showed comparable variant detection rates at 92.2% (n = 71/77) and 96.1% (n = 74/77), respectively. lrGS solely confirmed three repeat expansions with phased methylation data and enhanced accuracy in two complex structural variants. srGS detected six variants in homopolymeric regions that were missed by lrGS. Costing analysis revealed a comparable unit cost per sample for srGS and lrGS with USD1,545.97 and USD1,580.00, respectively. This study demonstrated that srGS excels in detecting variants near homopolymers while lrGS offers better resolution for complex variants and enables the simultaneous analysis of methylation and phasing. Although lrGS is not yet capable of fully replacing srGS, we anticipate that the continued technical improvement would position lrGS as the first‑tier genomic test for neurological disorders.
SN - 2056-7944
ER -