| Author | Casey, Ruth T. | |
| Author | Ascher, David Benjamin | |
| Author | Rattenberry, Eleanor | |
| Author | Izatt, Louise | |
| Author | Andrews, Katrina A. | |
| Author | Simpson, Helen L. | |
| Author | Challis, Benjamen | |
| Author | Park, Soo‐Mi | |
| Author | Bulusu, Venkata R. | |
| Author | Lalloo, Fiona | |
| Author | Pires, Douglas Eduardo Valente | |
| Author | West, Hannah | |
| Author | Clark, Graeme R. | |
| Author | Smith, Philip S. | |
| Author | Whitworth, James | |
| Author | Papathomas, Thomas G. | |
| Author | Taniere, Phillipe | |
| Author | Savisaar, Rosina | |
| Author | Hurst, Laurence D. | |
| Author | Woodward, Emma R. | |
| Author | Maher, Eamonn R. | |
| Access date | 2018-10-09T18:23:21Z | |
| Available date | 2018-10-09T18:23:21Z | |
| Document date | 2017 | |
| Citation | CASEY, Ruth T. et al. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity. Mol Genet Genomic Med., v. 5, n. 3, p. 237–250, 2017. | pt_BR |
| ISSN | 2324-9269 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/29479 | |
| Language | eng | pt_BR |
| Publisher | John Wiley & Sons | pt_BR |
| Rights | restricted access | pt_BR |
| Subject in Portuguese | Patogênese | pt_BR |
| Subject in Portuguese | SDHA | pt_BR |
| Subject in Portuguese | variante | pt_BR |
| Title | SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity | pt_BR |
| Type | Article | |
| DOI | 10.1002/mgg3.279 | |
| Abstract | Purpose: To evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.
Patients and methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of SDHA missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 “control missense variants” were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions.
Results: Literature review revealed reports of 17 different germline SDHA variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare SDHA missense variants present in a control data set (ESP6500) were also associated with impaired protein stability.
Conclusion: The clinical spectrum of SDHA‐associated neoplasia differs from that of germline mutations in other SDH‐subunits. The interpretation of the significance of novel SDHA missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management. | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK/Department of Endocrinology. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Addenbrooke's Hospital. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Biochemistry. University of Cambridge. Sanger Building. Cambridge, CB2 1GA, UK/Department of Biochemistry. Bio21 Institute. University of Melbourne. Melbourne, Victoria, 3010, Australia | pt_BR |
| Affilliation | West Midlands Region Genetics Service. Birmingham Women's Hospital. Birmingham, UK | pt_BR |
| Affilliation | Department of Medical Genetics. Guy's Hospital. London, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Oncology Centre. Cambridge University Hospitals. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Manchester Centre for Genomic Medicine. St Mary's Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester Academic Health Science Centre. Manchester, UK | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Affilliation | Department of Histopathology. King's College Hospital. London, UK | pt_BR |
| Affilliation | Histopathology and Cellular Pathology. University Hospitals Birmingham NHS Foundation Trust. Queen Elizabeth Hospital. Birmingham, UK | pt_BR |
| Affilliation | The Milner Centre for Evolution. Department of Biology and Biochemistry. University of Bath. Bath, BA2 7AY, UK | pt_BR |
| Affilliation | The Milner Centre for Evolution. Department of Biology and Biochemistry. University of Bath. Bath, BA2 7AY, UK | pt_BR |
| Affilliation | West Midlands Region Genetics Service. Birmingham Women's Hospital. Birmingham, UK/ Manchester Centre for Genomic Medicine. St Mary's Hospital. Central Manchester University Hospitals NHS Foundation Trust. Manchester Academic Health Science Centre. Manchester, UK | pt_BR |
| Affilliation | Department of Medical Genetics. University of Cambridge and NIHR Cambridge Biomedical Research Centre. Cambridge, CB2 2QQ, UK | pt_BR |
| Subject | Pathogenesis | pt_BR |
| Subject | SDHA | pt_BR |
| Subject | variant | pt_BR |
| Embargo date | 2022-01-01 | |
