de Bruijn Suzanne E, Ingeborgh van den Born L, Derks Ronny, Haer-Wigman Lonneke, O'Gorman Luke, Cremers Frans P M, van Beek Ronald, Hoischen Alexander, Roosing Susanne, Neveling Kornelia
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
The Rotterdam Eye Hospital and Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands.
NPJ Genom Med. 2025 Apr 22;10(1):33. doi: 10.1038/s41525-025-00490-8.
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.
Senior-Løken综合征是一种罕见的纤毛病，其特征为视网膜营养不良和肾单位肾痨。这种常染色体隐性遗传病由包括IQCB1在内的多个基因的致病变异引起。我们报告了一例Senior-Løken病例，在进行包括外显子组和基因组测序在内的常规基因检测后，其遗传病因仍未明确。为了确定该个体的遗传病因，我们采用了多种创新的长读长技术。通过光学基因组图谱分析，发现IQCB1基因内含子有一个6.2 kb的插入。长读长基因组测序验证确定该插入由一个LINE-1/ERV1移动元件组成。该变异与之前外显子组测序鉴定出的一个致病性IQCB1基因2 bp缺失呈反式。为了研究该插入的后果，我们进行了靶向长读长RNA测序，发现了一个复杂的剪接缺陷，导致提前引入终止密码子。这一发现表明，移动元件插入代表了一种尚未被充分认识的变异类型，使用短读长测序很难检测到。
