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<p>Senior-Løken syndrome is a rare ciliopathy characterized by retinal dystrophy and nephronophthisis. This autosomal recessive inherited disease is caused by pathogenic variants in several genes, including <i>IQCB1</i>. We present a Senior-Løken case that remained genetically unexplained after routine genetic testing, including exome and genome sequencing. To identify the genetic cause for this individual, a combination of innovative long-read technologies was employed. Using optical genome mapping, an intronic 6.2-kb insertion in <i>IQCB1</i> was revealed. Validation by long-read genome sequencing determined that this insertion consisted of a LINE-1/ERV1-mobile element. The variant was found in trans with a pathogenic <i>IQCB1</i> 2-bp deletion previously identified by exome sequencing. To investigate the consequences of the insertion, targeted long-read RNA-sequencing was performed, revealing a complex splice defect causing the introduction of a premature stop codon. This finding suggests that mobile element insertions represent a yet underestimated variant type that is difficult to detect using short-read sequencing.</p>

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Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome

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  • 出版模式：

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  • 发表日期：

    2025年4月22日

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  • Suzanne E. de Bruijn,
  • L. Ingeborgh van den Born,
  • Ronny Derks,
  • Lonneke Haer-Wigman,
  • Luke O’Gorman,
  • Frans P. M. Cremers,
  • Ronald van Beek,
  • Alexander Hoischen,
  • Susanne Roosing,
  • Kornelia Neveling

摘要

Senior-Løken syndrome is a rare ciliopathy characterized by retinal dystrophy and nephronophthisis. This autosomal recessive inherited disease is caused by pathogenic variants in several genes, including IQCB1. We present a Senior-Løken case that remained genetically unexplained after routine genetic testing, including exome and genome sequencing. To identify the genetic cause for this individual, a combination of innovative long-read technologies was employed. Using optical genome mapping, an intronic 6.2-kb insertion in IQCB1 was revealed. Validation by long-read genome sequencing determined that this insertion consisted of a LINE-1/ERV1-mobile element. The variant was found in trans with a pathogenic IQCB1 2-bp deletion previously identified by exome sequencing. To investigate the consequences of the insertion, targeted long-read RNA-sequencing was performed, revealing a complex splice defect causing the introduction of a premature stop codon. This finding suggests that mobile element insertions represent a yet underestimated variant type that is difficult to detect using short-read sequencing.