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

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.