Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome
| العنوان: | Long-Read Sequencing Identifies Novel Pathogenic Intronic Variants in Gitelman Syndrome |
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| المؤلفون: | Viering, D.H.H.M., Hureaux, M., Neveling, K., Latta, F., Kwint, M.P., Blanchard, A., Konrad, M., Bindels, R.J.M., Schlingmann, K.P., Vargas-Poussou, R., Baaij, J.H.F. de |
| المصدر: | Journal of the American Society of Nephrology, 34, 333-345 Journal of the American Society of Nephrology, 34, 2, pp. 333-345 |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | All institutes and research themes of the Radboud University Medical Center, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Nephrology, General Medicine |
| الوصف: | Item does not contain fulltext BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3 , which encodes the Na + -Cl - cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield. METHODS: Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants. RESULTS: A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns. CONCLUSION: Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome. |
| تدمد: | 1046-6673 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad07048e8396eae84f15299810c00f74 https://doi.org/10.1681/ASN.2022050627 |
| حقوق: | RESTRICTED |
| رقم الأكسشن: | edsair.doi.dedup.....ad07048e8396eae84f15299810c00f74 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10466673 |
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