Mosaic RASopathies: comprehensive genetic and clinicopathological analysis for diagnosis and management
6 affiliations
- 1N.N. Blokhin National Medical Research Center of Oncology , ,
- 2Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences , ,
- 3Research Center for Medical Genetics , ,
- 4Russian Children’s Clinical Hospital of Pirogov Russian National Research Medical University , ,
- 5N. N. Burdenko National Medical Research Center of Neurosurgery , ,
- 6St.Petersburg Clinical Scientific and Practical Centre for Special Types of Medical Care (Oncology) Named After N.P.Napalkov , ,
Abstract
Introduction
Mosaic RASopathies are rare conditions caused by postzygotic mutations arising during embryonic development in genes of the RAS/MAPK signaling pathway. They are mainly characterized by a combination of epidermal nevi and extracutaneous manifestations. Distinguishing between different entities can be challenging because of their substantial clinical and genetic overlap. Our aim was to demonstrate the importance of genetic background for accurate diagnosis and further prognostic assessment of disease progression by analyzing genotype-phenotype correlations within this clinical group.Methods
The study enrolled 18 patients (10 male and 8 female patients) ranging in age from 1 month to 21 years with congenital craniofacial nevi and variable extracutaneous abnormalities. DNA isolated from peripheral blood leukocytes and affected tissues (nevus and tumor) was analyzed using a targeted next-generation sequencing (NGS) panel covering RAS/MAPK pathway genes, followed by Sanger sequencing.Results
Eight patients were diagnosed with Schimmelpenning-Feuerstein-Mims syndrome caused by postzygotic pathogenic/likely pathogenic variants in the HRAS (n = 4) or KRAS (n = 4) genes. Seven patients were clinically diagnosed with phacomatosis pigmentokeratotica (PPK), and mosaic genetic variants were identified in the HRAS (n = 4), KRAS (n = 2), or BRAF (n = 1) genes. In two additional patients with similar phenotypes, somatic mutations in PIK3CA (n = 1) and FGFR2 (n = 1) were identified in affected skin, while in one further case, no clinically significant variant was detected.Discussion
We compared the spectrum of extracutaneous anomalies according to the affected gene by combining our data with data from other clinical cases of mosaic RASopathies described in the literature. In summary, 53 cases with HRAS postzygotic variants and 41 cases with KRAS variants were included in the analysis of genotype-phenotype correlations. Hypophosphatemic rickets (HR) and malignant tumors were associated with pathogenic/likely pathogenic variants in the HRAS gene, while ophthalmological, neurological, cardiovascular, and renal disorders were more common in KRAS-mutant patients.Conclusion
Thus, genetic testing of affected tissue in comparison to normal tissue (peripheral blood) is essential for accurate diagnosis of these mosaic disorders. Consideration of clinical manifestations and the identified genotype-phenotype correlations may further assist in determining prognosis and guiding patient management.
Related
- A comprehensive genetic study of the vaginal microbiota composition of Holstein cows
- The analysis of genetic variants in nine patients with nemaline myopathy: implications for diagnosis and genetic counseling
- Current translational perspectives for diagnosis and individualized therapy in rare genetic diseases
- Diagnosis of genetic ataxias in adulthood: protocol for a systematic review.
- Long-Term Experience in the Molecular Genetic Diagnosis of Friedreich Ataxia in the Russian Federation
BibTeX
@article{belysheva2026mosaic,
title = {{Mosaic RASopathies: comprehensive genetic and clinicopathological analysis for diagnosis and management}},
author = {Tatiana Belysheva and Tatiana Nasedkina and Ekaterina Zelenova and Vera Semenova and Natalia Semenova and Garik Sagoyan and Irina Kletskaya and Yana Vishnevskaya and Elena Sharapova and Kristina Kulikova and Pavel Vlasov and Alexandra Botkina and Margarita Belogurova and Marina Dorofeeva and Timur Valiev and Svetlana Varfolomeeva},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1908228},
url = {https://europepmc.org/article/PMC/PMC13716791},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mosaic RASopathies: comprehensive genetic and clinicopathological analysis for diagnosis and management
AU - Tatiana Belysheva
AU - Tatiana Nasedkina
AU - Ekaterina Zelenova
AU - Vera Semenova
AU - Natalia Semenova
AU - Garik Sagoyan
AU - Irina Kletskaya
AU - Yana Vishnevskaya
AU - Elena Sharapova
AU - Kristina Kulikova
AU - Pavel Vlasov
AU - Alexandra Botkina
AU - Margarita Belogurova
AU - Marina Dorofeeva
AU - Timur Valiev
AU - Svetlana Varfolomeeva
PY - 2026
DA - 2026/10/15
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1908228
UR - https://europepmc.org/article/PMC/PMC13716791
AB - Introduction Mosaic RASopathies are rare conditions caused by postzygotic mutations arising during embryonic development in genes of the RAS/MAPK signaling pathway. They are mainly characterized by a combination of epidermal nevi and extracutaneous manifestations. Distinguishing between different entities can be challenging because of their substantial clinical and genetic overlap. Our aim was to demonstrate the importance of genetic background for accurate diagnosis and further prognostic assessment of disease progression by analyzing genotype-phenotype correlations within this clinical group.Methods The study enrolled 18 patients (10 male and 8 female patients) ranging in age from 1 month to 21 years with congenital craniofacial nevi and variable extracutaneous abnormalities. DNA isolated from peripheral blood leukocytes and affected tissues (nevus and tumor) was analyzed using a targeted next-generation sequencing (NGS) panel covering RAS/MAPK pathway genes, followed by Sanger sequencing.Results Eight patients were diagnosed with Schimmelpenning-Feuerstein-Mims syndrome caused by postzygotic pathogenic/likely pathogenic variants in the HRAS (n = 4) or KRAS (n = 4) genes. Seven patients were clinically diagnosed with phacomatosis pigmentokeratotica (PPK), and mosaic genetic variants were identified in the HRAS (n = 4), KRAS (n = 2), or BRAF (n = 1) genes. In two additional patients with similar phenotypes, somatic mutations in PIK3CA (n = 1) and FGFR2 (n = 1) were identified in affected skin, while in one further case, no clinically significant variant was detected.Discussion We compared the spectrum of extracutaneous anomalies according to the affected gene by combining our data with data from other clinical cases of mosaic RASopathies described in the literature. In summary, 53 cases with HRAS postzygotic variants and 41 cases with KRAS variants were included in the analysis of genotype-phenotype correlations. Hypophosphatemic rickets (HR) and malignant tumors were associated with pathogenic/likely pathogenic variants in the HRAS gene, while ophthalmological, neurological, cardiovascular, and renal disorders were more common in KRAS-mutant patients.Conclusion Thus, genetic testing of affected tissue in comparison to normal tissue (peripheral blood) is essential for accurate diagnosis of these mosaic disorders. Consideration of clinical manifestations and the identified genotype-phenotype correlations may further assist in determining prognosis and guiding patient management.
SN - 2296-634X
ER -