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<p>Genome sequencing (GS) often reveals non-coding variants of uncertain significance, especially those predicted to affect pre-mRNA splicing. We present an integrative workflow combining splice prediction, a minigene assay and long-read RNA sequencing to assess their functional impact. Applied to a <i>de novo</i> heterozygous 17-bp intronic deletion in <i>FOXP1</i> from a child with a neurodevelopmental disorder, this approach showed impaired exon recognition and multiple aberrant transcript isoforms, supporting a loss-of-function mechanism consistent with <i>FOXP1</i> haploinsufficiency. Our results illustrate how experimental and isoform-resolved transcriptomic analyses can refine the interpretation of non-coding splice-altering variants detected by GS in clinical genomics.</p>

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Resolving non‑coding splice‑altering variants using an integrative genomic and transcriptomic workflow: application to FOXP1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Pauline Planté-Bordeneuve,
  • Anne-Sophie Jourdain,
  • Caroline Thuillier,
  • Aurélien Caux,
  • Marine Tessarech,
  • Jean-Pascal Meneboo,
  • Emilie Ait-Yahya,
  • Sara Costantini,
  • Perrine Brunelle,
  • Thomas Smol

摘要

Genome sequencing (GS) often reveals non-coding variants of uncertain significance, especially those predicted to affect pre-mRNA splicing. We present an integrative workflow combining splice prediction, a minigene assay and long-read RNA sequencing to assess their functional impact. Applied to a de novo heterozygous 17-bp intronic deletion in FOXP1 from a child with a neurodevelopmental disorder, this approach showed impaired exon recognition and multiple aberrant transcript isoforms, supporting a loss-of-function mechanism consistent with FOXP1 haploinsufficiency. Our results illustrate how experimental and isoform-resolved transcriptomic analyses can refine the interpretation of non-coding splice-altering variants detected by GS in clinical genomics.