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<p>Up to 17% of neurodevelopmental disorders (NDDs) can be explained by pathogenic structural variants (SVs) that disrupt coding regions and elicit gene dosage defects. However, noncoding SVs which can perturb <i>cis</i>-regulatory elements (CREs) and downstream gene expression are understudied. In this study, we describe multiple 14q12 deletions downstream of NDD-related gene <i>FOXG1</i> in individuals with overlapping phenotypes of <i>FOXG1</i> haploinsufficiency. We show that deletion of a minimum region of overlap (MRO) reduced <i>FOXG1</i> expression, disrupted CREs and altered <i>FOXG1</i>’s native genomic interactions. Deleting the MRO did not fully eliminate <i>FOXG1</i> expression, indicating that multiple CREs likely cooperate to regulate <i>FOXG1</i> and would need to be deleted to completely prevent expression. The transcriptomic profiles of MRO loss overlap in part with <i>FOXG1</i> loss, including direct FOXG1 targets, indicating converging molecular pathways. These findings expand the scope of <i>FOXG1’s</i> complex regulatory region, and more broadly, of regulatory SVs in NDD susceptibility.</p>

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Analysis of 14q12 microdeletions reveals novel regulatory loci for the neurodevelopmental disorder-related gene FOXG1

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月21日

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  • Aishwarya Ramamurthy,
  • Mash D. Bandouil,
  • Likhita Aluru,
  • Ojasi Joshi,
  • Esther Yoon,
  • Nicholas Bodkin,
  • Jennifer Z. Cheng,
  • Carina G. Biar,
  • Jeffrey D. Calhoun,
  • Gemma L. Carvill

摘要

Up to 17% of neurodevelopmental disorders (NDDs) can be explained by pathogenic structural variants (SVs) that disrupt coding regions and elicit gene dosage defects. However, noncoding SVs which can perturb cis-regulatory elements (CREs) and downstream gene expression are understudied. In this study, we describe multiple 14q12 deletions downstream of NDD-related gene FOXG1 in individuals with overlapping phenotypes of FOXG1 haploinsufficiency. We show that deletion of a minimum region of overlap (MRO) reduced FOXG1 expression, disrupted CREs and altered FOXG1’s native genomic interactions. Deleting the MRO did not fully eliminate FOXG1 expression, indicating that multiple CREs likely cooperate to regulate FOXG1 and would need to be deleted to completely prevent expression. The transcriptomic profiles of MRO loss overlap in part with FOXG1 loss, including direct FOXG1 targets, indicating converging molecular pathways. These findings expand the scope of FOXG1’s complex regulatory region, and more broadly, of regulatory SVs in NDD susceptibility.