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<p>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% (<i>n</i> = 70/310, 77 variants). lrGS and srGS showed comparable variant detection rates at 92.2% (<i>n</i> = 71/77) and 96.1% (<i>n</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Dream Lok Sze Chan,
  • Helen Ying Fung Tam,
  • Amy Hin Yan Tong,
  • Wei Ma,
  • Chak Sing Lau,
  • Ho Ming Luk,
  • Shirley Yin Yu Pang,
  • Shirley Sze Wing Cheng,
  • Yuan Gao,
  • Lai Ting Leung,
  • Denis Long Him Yeung,
  • Claudia Ching Yan Chung,
  • Steve Tsz Fung Chan,
  • Shirley Pik Ying Hue,
  • Anson Man Chun Xi,
  • Dicky Or,
  • Steve Cheuk Yiu Yeung,
  • Jamie Sui Lam Kwok,
  • Nattily Sum Yin Tai,
  • Carol Ching Fun Lau,
  • Wai Lap Wong,
  • Raven Yan Wah Lee,
  • Janice Kai Ning Wong,
  • Hong Kong Genome Project,
  • Annie Tsz Wai Chu,
  • Brian Hon Yin Chung

摘要

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.