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Background <p>Inherited retinal dystrophies (IRDs) are a genetically heterogeneous group of conditions, with approximately 40% of cases remaining unresolved after initial genetic testing. This study aimed to assess the impact of a personalised genomic approach integrating whole-exome sequencing (WES) reanalysis, whole-genome sequencing (WGS), customised gene panels and functional assays to improve diagnostic yield in unresolved cases.</p> Subjects/Methods <p>We retrospectively reviewed a cohort of 597 individuals with IRDs, including 525 probands and 72 affected relatives. Among the 221 genetically unresolved cases, a subset of 101 was selected for stepwise re-evaluation. This included WES reanalysis with updated virtual panels, WGS in selected cases and targeted sequencing of complex regions. Variant interpretation was refined using updated classification criteria, segregation analysis and functional assays such as mRNA and minigene/midigene studies.</p> Results <p>An initial diagnostic yield of 59.6% (313/525) was achieved through first-tier genetic testing. Re-evaluation of the 101 prioritised cases resulted in 42 new diagnoses in probands and resolution of 7 more familial cases, yielding 49 additional diagnoses among previously unresolved patients (48.5%). This increased the overall diagnostic rate for probands to 67.6% (355/525). Functional assays confirmed pathogenicity of variants in <i>ABCA4</i>, <i>ATF6</i>, <i>REEP6,</i> and <i>TULP1</i>, while WGS enabled the detection of structural and deep intronic variants, further enhancing diagnostic accuracy.</p> Conclusions <p>A patient-centred, stepwise genomic approach significantly improved the molecular diagnosis of IRDs. This strategy supports the clinical utility of periodic WES reanalysis and targeted use of customised panels, WGS and functional assays. The proposed workflow is scalable and applicable to routine clinical practice, contributing to precision medicine in IRDs.</p>

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Personalised genomic strategies improve diagnostic yield in inherited retinal dystrophies: a stepwise, patient-centred approach

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月9日

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  • Anna Esteve-Garcia,
  • Ariadna Padró-Miquel,
  • Jaume Català-Mora,
  • Cristina Sau,
  • Delia Yubero,
  • Zelia Corradi,
  • Frans P. M. Cremers,
  • Pilar Barberán-Martínez,
  • José M. Millán,
  • Gema García-García,
  • Ilyana Ismael,
  • Luis Arias,
  • Estefania Cobos,
  • Cinthia Aguilera

摘要

Background

Inherited retinal dystrophies (IRDs) are a genetically heterogeneous group of conditions, with approximately 40% of cases remaining unresolved after initial genetic testing. This study aimed to assess the impact of a personalised genomic approach integrating whole-exome sequencing (WES) reanalysis, whole-genome sequencing (WGS), customised gene panels and functional assays to improve diagnostic yield in unresolved cases.

Subjects/Methods

We retrospectively reviewed a cohort of 597 individuals with IRDs, including 525 probands and 72 affected relatives. Among the 221 genetically unresolved cases, a subset of 101 was selected for stepwise re-evaluation. This included WES reanalysis with updated virtual panels, WGS in selected cases and targeted sequencing of complex regions. Variant interpretation was refined using updated classification criteria, segregation analysis and functional assays such as mRNA and minigene/midigene studies.

Results

An initial diagnostic yield of 59.6% (313/525) was achieved through first-tier genetic testing. Re-evaluation of the 101 prioritised cases resulted in 42 new diagnoses in probands and resolution of 7 more familial cases, yielding 49 additional diagnoses among previously unresolved patients (48.5%). This increased the overall diagnostic rate for probands to 67.6% (355/525). Functional assays confirmed pathogenicity of variants in ABCA4, ATF6, REEP6, and TULP1, while WGS enabled the detection of structural and deep intronic variants, further enhancing diagnostic accuracy.

Conclusions

A patient-centred, stepwise genomic approach significantly improved the molecular diagnosis of IRDs. This strategy supports the clinical utility of periodic WES reanalysis and targeted use of customised panels, WGS and functional assays. The proposed workflow is scalable and applicable to routine clinical practice, contributing to precision medicine in IRDs.