Clinical RNA sequencing clarifies variants of uncertain significance identified by prior testing.

Autor:	Marquez J; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Cech JN; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Paschal CR; Department of Laboratories, Seattle Children's Hospital, Seattle, WA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA., Dingmann B; Division of Developmental Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Scott AI; Department of Laboratories, Seattle Children's Hospital, Seattle, WA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA., Thies JM; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Mills MR; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Albert CM; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Washington, Seattle, WA.; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA., Beck AE; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Beckman E; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Bonkowski ES; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN., Earl DL; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Lam CT; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Mefford HC; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN., Merritt JL 2nd; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Nelson Z; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Ohlsen TJ; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Washington, Seattle, WA.; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA., Taylor MR; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Washington, Seattle, WA.; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA., Perlman SJ; Division of Pediatric Neurology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Rudzinski ER; Department of Laboratories, Seattle Children's Hospital, Seattle, WA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA., Sikes MC; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Waligorski N; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Wenger TL; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Adam MP; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA., Mirzaa GM; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA., Bennett JT; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA.; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA., Glass IA; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA.; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA., Sternen DL; Department of Laboratories, Seattle Children's Hospital, Seattle, WA., Miller DE; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.; Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA.
Jazyk:	angličtina
Zdroj:	Genetics in medicine open [Genet Med Open] 2024; Vol. 2. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1016/j.gimo.2024.101886
Abstrakt:	Purpose: Sequencing-based genetic testing often identifies variants of uncertain significance (VUS) or fails to detect pathogenic variants altogether. We evaluated the utility of RNA sequencing (RNA-seq) to clarify VUS or identify missing variants in a clinical setting. Methods: Over a 2-year period, genetics providers at a single institution referred 26 cases for clinical RNA-seq. Cases had either no candidate variant identified by prior testing or a VUS suspected to impact splicing or expression. A committee reviewed each submission to ensure it met study criteria. Results: Among 26 cases, 8 could not be sequenced because of poor expression in an accessible tissue, 2 did not meet inclusion criteria, 3 were solved prior to collection, and 4 families declined participation or did not complete sample collection. For the 9 cases sequenced, the clinical laboratory reported two positive, four negative, and three "indeterminate." For all three indeterminate cases, original RNA-seq data was manually evaluated and deemed explanatory. Conclusion: Clinical RNA-seq can clarify VUS, especially splice variants, but laboratory-specific interpretation guidelines may lead to indeterminate results. Identifying individuals likely to benefit from RNA-seq and providing appropriate counseling poses unique challenges. Competing Interests: DEM holds stock options in MyOme, is on a scientific advisory board at Oxford Nanopore Technologies (ONT), is engaged in a research agreement with ONT, and has received travel support from ONT.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu