
Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic KRAS Variation
Author(s) -
Selma Demir,
Hümeyra Yaşar Köstek,
Aslıhan Sanri,
Ruken Yıldırım,
Fatma Özgüç Çömlek,
Sinem Yalçıntepe,
Murat Devecí,
Emine İkbal Atlı,
Engin Atlı,
Damla Eker,
Hakan Gürkan,
Filiz Tütüncüler Kökenli
Publication year - 2022
Publication title -
molecular syndromology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.609
H-Index - 36
eISSN - 1661-8777
pISSN - 1661-8769
DOI - 10.1159/000520722
Subject(s) - kras , hras , neuroblastoma ras viral oncogene homolog , medicine , genetics , mutation , biology , gene
Germline pathogenic variations of the genes encoding the components of the Ras-MAPK pathway are found to be responsible for RASopathies, a clinically and genetically heterogeneous group of diseases. In this study, we aimed to present the results of patients genetically investigated for RASopathy-related mutations in our Genetic Diagnosis Center. Methods: The results of 51 unrelated probands with RASopathy and 4 affected relatives (31 male, 24 female; mean age: 9.327 ± 8.214) were included in this study. Mutation screening was performed on DNA samples from peripheral blood of the patients either by Sanger sequencing of PTPN11 hotspot regions (10/51 probands), or by a targeted amplicon next-generation sequencing panel (41/51 probands) covering the exonic regions of BRAF , CBL , HRAS , KRAS , LZTR1 , MAP2K1 , MAP2K2 , NF1 , NRAS , PTPN11 , RAF1 , RASA2 , RIT1 , SHOC2 , SOS1 , SOS2 , SPRED1 , and KAT6B genes. Results: Pathogenic/likely pathogenic variations found in 22 out of 51 probands (43.13%) and their 4 affected family members were located in PTPN11 , BRAF , KRAS , NF1 , RAF1 , SOS1 , and SHOC2 genes. The c.148A>C (p.Thr50Pro) variation in the KRAS gene was a novel variant detected in a sibling in our patient cohort. We found supportive evidence for the pathogenicity of the NF1 gene c.5606G>T (p.Gly1869Val) variation which we defined in an affected boy who inherited the mutation from his affected father. Conclusion: Although PTPN11 is the most frequently mutated gene in our patient cohort, as in most previous reports, different mutation distribution among the other genes studied motivates the use of a next-generation sequencing gene panel including the possible responsible genes.