Here, we report a crystal structure of GDP-bound KRAS<sup>V14I</sup>, a mutated KRAS variant associated with the developmental RASopathy disorder Noonan syndrome (NS), at 1.5-1.6 Å resolution.
Gene-related Chinese NS facial features were described using artificial intelligence (AI).NGS identified pathogenic variants in 103 Chinese patients in eight NS-related genes: PTPN11 (48.5%), SOS1 (12.6%), SHOC2 (11.7%), KRAS (9.71%), RAF1 (7.77%), RIT1 (6.8%), CBL (0.97%), NRAS (0.97%), and LZTR1 (0.97%).
Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder that is phenotypically similar to Noonan syndrome and is associated with mutations in BRAF, MEK1, MEK2, and KRAS.
Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome.
The scope of cardiac disease in Noonan syndrome is quite variable depending on the gene mutation, with some mutations usually associated with a high incidence of congenital heart defects (PTPN11, KRAS, and others) while those with predominantly hypertrophic cardiomyopathy (HCM) have higher risk and morbidity profiles (RAF1, RIT1, and those associated with multiple lentigines).
Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported.
We have previously developed and characterized a knock-in mouse model that carries one of the most frequent KRAS-NS-related mutations, the K-Ras(V14I) substitution, which recapitulates most of the alterations described in NS patients, including MPDs.
The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.
K-Ras(V14I)-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML.
K-Ras(V14I)-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML.
Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene.
RASopathies (Noonan syndrome (NS) and Noonan-related syndromes) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway (PTPN11, SOS1, RAF, KRAS or NRAS, and SHOC2).
Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations.
Anthropometric measurements (mean of 4.3 measurements per patient) were obtained in a mixed cross-sectional and longitudinal mode from 127 NS and 10 NLS patients with mutations identified in PTPN11 (n = 90), SOS1 (n = 14), RAF1 (n = 10), KRAS (n = 8), BRAF (n = 11), and SHOC2 (n = 4) genes.