Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/77618
Title: Integrating functional analysis in the next-generation sequencing diagnostic pipeline of RASopathies
Authors: Leung, GKC
Luk, HM
Tang, VHM
Gao, WW
Mak, CCY
Yu, MHC
Wong, WL
Chu, YWY
Yang, WL
Wong, WHS
Ma, ACH 
Leung, AYH
Jin, DY
Chan, KYK
Allanson, J
Lo, IFM
Chung, BHY
Issue Date: 2018
Source: Scientific reports, 5 2018, v. 8, no. 1, 2421, p. 1-9
Abstract: 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.
Publisher: Nature Publishing Group
Journal: Scientific reports 
EISSN: 2045-2322
DOI: 10.1038/s41598-018-20894-0
Rights: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2018
The following publication Leung, G.K.C., Luk, H.M., Tang, V.H.M. et al. Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies. Sci Rep 8, 2421 (2018) is available at https://dx.doi.org/10.1038/s41598-018-20894-0
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