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<p>The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in <i>EYA1</i> that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced <i>EYA1</i> transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.</p>

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The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Marie Lorans,
  • Kristian Alsbjerg Skipper,
  • Trine Østergaard Nielsen,
  • Simon Opstrup Drue,
  • Christine Kroer Nielsen,
  • Christian Vinberg Thorup,
  • Sven Erik Nørholt,
  • Lisbeth Marianne Thøstesen,
  • Pernille Axél Gregersen

摘要

The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.