High-Throughput Splicing Assays Identify Known and Novel WT1 Exon 9 Variants in Nephrotic Syndrome.
| Autor: | Smith C; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Burugula BB; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Dunn I; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Aradhya S; Invitae, San Francisco, California, USA., Kitzman JO; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Yee JL; Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Kidney international reports [Kidney Int Rep] 2023 Aug 05; Vol. 8 (10), pp. 2117-2125. Date of Electronic Publication: 2023 Aug 05 (Print Publication: 2023). |
| DOI: | 10.1016/j.ekir.2023.07.033 |
| Abstrakt: | Introduction: Frasier syndrome (FS) is a rare Mendelian form of nephrotic syndrome (NS) caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce 2 isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the 8 already known could cause FS. Methods: To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant ( n = 519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Results: Splice disruptive variants (SDVs) made up 11% of the tested point variants overall and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all 8 known FS or focal segmental glomerulosclerosis (FSGS) variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which 2 are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). Conclusion: This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon 9. (© 2023 International Society of Nephrology. Published by Elsevier Inc.) |
| Databáze: | MEDLINE |
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