What question did this study set out to answer?

This study aims to directly compare long-read genome sequencing (lrGS) and short-read genome sequencing (srGS) in diagnosing neurological disorders.

July 1, 2026npj Genomic Medicine0 citationsOpen Access

Systematic evaluation of long-read and short-read sequencing in neurological disorders diagnosis: a direct comparison study of 310 patients

DCDream Lok Sze ChanUniversity of Hong Kong HTHelen Ying Fung Tam ATAmy H.Y. TongUniversity of Toronto

Key Points

This study aims to directly compare long-read genome sequencing (lrGS) and short-read genome sequencing (srGS) in diagnosing neurological disorders.
Compared diagnostic performance of lrGS and srGS in 310 families with undiagnosed neurological disorders
Analyzed variant detection rates and technical capabilities for both sequencing types
Conducted a costing analysis of per-sample sequencing expenses.
Overall diagnostic yield was 22.6% (n=70/310, 77 variants) with comparable variant detection rates: lrGS 92.2% (n=71/77) and srGS 96.1% (n=74/77)
lrGS confirmed three repeat expansions and enhanced accuracy in two complex structural variants
Cost per sample: srGS at USD1,545.97 and lrGS at USD1,580.00, showing minimal cost difference.

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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