Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome
Abstract 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 routi...
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| Format: | Article |
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Nature Portfolio
2025-04-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-025-00490-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Suzanne E. de Bruijn |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-413d84ccf2b64a87b41ecedae00490d8 |
| institution | OA Journals |
| issn | 2056-7944 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj-art-413d84ccf2b64a87b41ecedae00490d82025-08-20T02:19:58ZengNature Portfolionpj Genomic Medicine2056-79442025-04-011011510.1038/s41525-025-00490-8Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndromeSuzanne E. de Bruijn0L. Ingeborgh van den Born1Ronny Derks2Lonneke Haer-Wigman3Luke O’Gorman4Frans P. M. Cremers5Ronald van Beek6Alexander Hoischen7Susanne Roosing8Kornelia Neveling9Department of Human Genetics, Radboud University Medical CenterThe Rotterdam Eye Hospital and Rotterdam Ophthalmic InstituteDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterAbstract 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.https://doi.org/10.1038/s41525-025-00490-8 |
| spellingShingle | 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 Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome npj Genomic Medicine |
| title | Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome |
| title_full | Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome |
| title_fullStr | Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome |
| title_full_unstemmed | Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome |
| title_short | Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome |
| title_sort | long read technologies identify a hidden line 1 erv1 insertion in iqcb1 as causative variant for senior loken syndrome |
| url | https://doi.org/10.1038/s41525-025-00490-8 |
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