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<p>The broad genetic heterogeneity of neurodevelopmental disorders (NDDs) makes their molecular diagnosis particularly challenging. In this context, Whole-Exome Sequencing (WES), specifically in a trio-based design, is a powerful strategy due to its ability to detect de novo variants, which are a major contributor to NDDs. However, its clinical implementation is often limited by its associated cost. In this study, we applied a sequential diagnostic workflow to a cohort of 221 individuals with syndromic NDDs and prior negative results from targeted sequencing. The workflow integrates initial solo-WES, followed by a second-tier trio-WES using pooled parental DNA (trio pooled-WES). Overall, this workflow achieved a diagnostic yield of 20.98% and led to the identification of 13 novel candidate genes. The pooling strategy was optimized and validated, demonstrating that trio pooled-WES retains the main advantages of conventional trio-WES while substantially reducing sequencing costs. These results support its implementation as a clinically applicable approach for the genetic diagnosis of NDDs.</p>

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Accurate and cost-effective workflow integrating trio pooled-WES for novel gene discovery in neurodevelopmental disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Lucía López-López,
  • Laura Lapeña-Gil,
  • Yolanda Benítez,
  • Caridad Serrano,
  • Ana Isabel Sánchez-Barbero,
  • Fiona Blanco-Kelly,
  • Fermina López-Grondona,
  • Saoud Tahsin-Swafiri,
  • Isabel Lorda-Sánchez,
  • Carmen Ayuso,
  • Pablo Mínguez,
  • Berta Almoguera

摘要

The broad genetic heterogeneity of neurodevelopmental disorders (NDDs) makes their molecular diagnosis particularly challenging. In this context, Whole-Exome Sequencing (WES), specifically in a trio-based design, is a powerful strategy due to its ability to detect de novo variants, which are a major contributor to NDDs. However, its clinical implementation is often limited by its associated cost. In this study, we applied a sequential diagnostic workflow to a cohort of 221 individuals with syndromic NDDs and prior negative results from targeted sequencing. The workflow integrates initial solo-WES, followed by a second-tier trio-WES using pooled parental DNA (trio pooled-WES). Overall, this workflow achieved a diagnostic yield of 20.98% and led to the identification of 13 novel candidate genes. The pooling strategy was optimized and validated, demonstrating that trio pooled-WES retains the main advantages of conventional trio-WES while substantially reducing sequencing costs. These results support its implementation as a clinically applicable approach for the genetic diagnosis of NDDs.