Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis
| Autor: | Ilana Moscatelli, Kim Henriksen, Odelia Chorin, Naomi Yachelevich, Gilad D. Evrony, John Pappas, Khaled Mohamed |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty lcsh:QH426-470 medicine.medical_treatment RNA Splicing Osteoclasts Genes Recessive Hematopoietic stem cell transplantation RNA‐sequencing 030105 genetics & heredity Biology Clinical Reports Transcriptome 03 medical and health sciences transcriptomics Osteoclast Chloride Channels Genetics medicine Humans Genetic Testing RNA-Seq Molecular Biology Genetics (clinical) Loss function Genetic testing Clinical Report medicine.diagnostic_test Osteopetrosis medicine.disease undiagnosed diseases Introns 3. Good health lcsh:Genetics 030104 developmental biology medicine.anatomical_structure Child Preschool biology.protein Medical genetics Female CLCN7 |
| Zdroj: | Molecular Genetics & Genomic Medicine Molecular Genetics & Genomic Medicine, Vol 8, Iss 10, Pp n/a-n/a (2020) |
| ISSN: | 2324-9269 |
| Popis: | Background Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA‐based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole‐genome sequencing was nondiagnostic. Methods We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies. Results We identified a pathogenic deep intronic variant in CLCN7 creating an unexpected, frameshifting pseudoexon causing complete loss of function. Functional studies, including osteoclastogenesis and bone resorption assays, confirmed normal osteoclast differentiation but loss of osteoclast function. Conclusion This is the first report of a pathogenic deep intronic variant in CLCN7, and our approach provides a model for systematic identification of noncoding variants causing osteopetrosis—a disease for which molecular‐genetic diagnosis can be pivotal for potentially curative hematopoietic stem cell transplantation. Our work illustrates that cryptic splice variants may elude DNA‐only sequencing and supports broad first‐line use of transcriptome sequencing for children with undiagnosed diseases. Over half of children with rare genetic diseases remain undiagnosed despite maximal DNA‐based genetic testing. Using transcriptome (RNA) sequencing, we identified a deep intronic variant in CLCN7 as the cause of a child's previously undiagnosed severe osteopetrosis syndrome. This work illustrates that cryptic splice variants may elude DNA‐only sequencing and supports first‐line use of transcriptome sequencing for undiagnosed diseases. |
| Databáze: | OpenAIRE |
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