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Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies.
- Source :
-
Scientific reports [Sci Rep] 2018 Feb 05; Vol. 8 (1), pp. 2421. Date of Electronic Publication: 2018 Feb 05. - Publication Year :
- 2018
-
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.
- Subjects :
- Adolescent
Animals
Biological Assay
Child
Child, Preschool
Computational Biology
Costello Syndrome pathology
Ectodermal Dysplasia pathology
Facies
Failure to Thrive pathology
Female
Gene Expression
Genetic Predisposition to Disease
Genome-Wide Association Study
Germ-Line Mutation
Heart Defects, Congenital pathology
High-Throughput Nucleotide Sequencing
Humans
Infant
MAP Kinase Kinase 1 genetics
Male
Mutation, Missense
Neurofibromatosis 1 pathology
Noonan Syndrome pathology
Proto-Oncogene Proteins p21(ras) genetics
SOS1 Protein genetics
Zebrafish
alpha-Macroglobulins genetics
Costello Syndrome genetics
Ectodermal Dysplasia genetics
Failure to Thrive genetics
Heart Defects, Congenital genetics
Neurofibromatosis 1 genetics
Noonan Syndrome genetics
Proto-Oncogene Proteins c-raf genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29402968
- Full Text :
- https://doi.org/10.1038/s41598-018-20894-0