The patient was a 7-year-old boy with NS, who was included in the first series reporting the association between Noonan and RAF1, and who later presented with a 2-week history of asymptomatic unilateral tonsillar swelling and ipsilateral cervical lymphadenopathy.
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).
The aim of the study was to assess various aspects of visual and visuoperceptual function in patients with Noonan syndrome (NS) or LEOPARD syndrome (LS) with mutations affecting the PTPN11, SOS1 and RAF1 genes.
Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general.
These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation.
In this study, we analyzed ten Chinese patients diagnosed with NS and related disorders and identified their correspondingPTPN11, RAF1, and BRAF mutations.
Recently, mutations in RAF1 have been also identified in patients with NS and two patients with LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome.
The aim of this study was to assess the correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with NS.
These findings suggest that duplications of genomic regions encompassing RAF1 could cause NS and are consistent with the notion that rare copy number variations encompassing causative genes may underlie a small percentage of patients with syndromic CHD like NS.
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).
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.
We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1(S259A)) that is associated with Noonan syndrome.
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%).
Taken together, the results of our study identify the molecular mechanisms by which NSRAF1 mutations cause HCM and reveal downstream effectors that could serve as therapeutic targets for treatment of NS and perhaps other, more common, congenital HCM disorders.
Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS.
PTPN11 (39.0%), SOS1 (20.3%), RAF1 (6.8%), KRAS (5.1%), and BRAF (1.7%) mutations were identified in NS; BRAF (41.2%), SHOC2 (23.5%), and MEK1 (5.9%) mutations in cardiofaciocutaneous syndrome; and HRAS and PTPN11 mutations in Costello syndrome and LEOPARD syndrome, respectively.
Noonan Syndrome (NS) is an autosomal dominant condition characterized by short stature, facial dysmorphisms, and congenital heart defects, and is caused by mutations in either PTPN11, KRAS, NRAS, SHOC2, RAF1, or SOS1.