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Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies.
Leung, Gordon K C; Luk, H M; Tang, Vincent H M; Gao, W W; Mak, Christopher C Y; Yu, Mullin H C; Wong, W L; Chu, Yoyo W Y; Yang, W L; Wong, Wilfred H S; Ma, Alvin C H; Leung, Anskar Y H; Jin, D Y; Chan, Kelvin Y K; Allanson, Judith; Lo, Ivan F M; Chung, Brian H Y.
Afiliación
  • Leung GKC; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Luk HM; Clinical Genetic Service, Department of Health, Hong Kong, China.
  • Tang VHM; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Gao WW; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Mak CCY; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Yu MHC; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Wong WL; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Chu YWY; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Yang WL; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Wong WHS; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Ma ACH; Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Leung AYH; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China.
  • Jin DY; Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Chan KYK; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Allanson J; Department of Obstetrics and Gynaecology, Tsan Yuk Hospital, Hong Kong, China.
  • Lo IFM; Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ontario, Canada.
  • Chung BHY; Clinical Genetic Service, Department of Health, Hong Kong, China. dr.ivanlo@gmail.com.
Sci Rep ; 8(1): 2421, 2018 02 05.
Article en En | MEDLINE | ID: mdl-29402968
RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Displasia Ectodérmica / Neurofibromatosis 1 / Proteínas ras / Proteínas Proto-Oncogénicas c-raf / Insuficiencia de Crecimiento / Síndrome de Costello / Cardiopatías Congénitas / Síndrome de Noonan Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Displasia Ectodérmica / Neurofibromatosis 1 / Proteínas ras / Proteínas Proto-Oncogénicas c-raf / Insuficiencia de Crecimiento / Síndrome de Costello / Cardiopatías Congénitas / Síndrome de Noonan Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Infant / Male Idioma: En Revista: Sci Rep Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido