Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.

The RASopathies are a group of disorders resulting from a germline variant in the genes encoding the Ras/mitogen-activated protein kinase pathway. These disorders include Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome (LS), and neurofibromatosis type 1 (NF1), and have overlapping clinical features due to RAS/MAPK dysfunction. In this study, we aimed to describe the clinical and molecular features of patients exhibiting phenotypic manifestations consistent with RASopathies. The study included 149 patients from 146 unrelated families who were admitted between 2019 and 2023 with a clinical suspicion of RASopathy spectrum disorder. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of twenty-four RASopathy genes was performed using a targeted next-generation sequencing (NGS) panel, and the variants were classified according to American College of Medical Genetics and Genomics Standards and Guidelines recommendations. Pathogenic/likely pathogenic variants were detected in 39 out of 149 patients (26.1%). Thirty-two patients were diagnosed as NS (32/39; 82%). The variants detected in NS patients were PTPN11 (21/32; 65.6%), LZTR1 (3/32; 9.3%), SOS1 (2/32; 6.2%), RAF1 (2/32; 6.2%), RIT1 (2/32; 6.2%), KRAS (1/32; 3.1%), and RRAS (1/32; 3.1%) genes, respectively. The remaining patients were diagnosed with CS (2/39; 5.1%), NF1 (2/39; 5.1%), NF-NS (2/39; 5.1%), and CFC (1/39; 2.5%). We observed rare clinical findings including lymphangioma circumscriptum, Meckel's diverticulum, and omphalocele in three patients with PTPN11 gene variations. Additionally, we detected corpus callosum thickness in a patient with the SOS1 gene variant, which has not been previously described in NS. We also identified three novel variants in RIT1, BRAF, and NF1 genes. In this study, we described rare clinical manifestations and detected three novel variants in NF1, BRAF, and RIT1 genes. We propose that NGS technology enables the detection of variants in rare genes responsible for the etiology of RASopathies. The study, therefore, not only contributes to the existing literature but also expands the spectrum of genotype and phenotype of RASopathies. • RASopathies are a group of disorders caused by germline variants in genes involved in the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway. • These disorders, including Noonan syndrome (NS), Cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome, and Neurofibromatosis type 1 (NF1), share overlapping clinical features due to RAS/MAPK dysfunction. Molecular diagnosis of RASopathies is crucial for understanding the genetic basis and guiding clinical management, although the phenotype-genotype relationships remain incompletely defined. • This study provides new insights into the molecular and clinical characteristics of RASopathies by examining 149 patients from 146 families, with a focus on the genetic variants found in 24 RASopathy-related genes. Three novel variants were identified in the RIT1, BRAF, and NF1 genes, expanding the genetic spectrum of RASopathies. • Additionally, rare clinical findings, such as lymphangioma circumscriptum and corpus callosum thickness, were reported in patients with PTPN11 and SOS1 gene variations, respectively. These observations contribute new phenotypic data to the existing body of knowledge.

Yılmaz Uzman C ，Gürsoy S ，Özkan B ，Vuran G ，Ayyıldız Emecen D ，Köprülü Ö ，Bilen MM ，Hazan F ... -  《-》

Noonan Syndrome.

Adam MP ，Feldman J ，Mirzaa GM ，Pagon RA ，Wallace SE ，Amemiya A ，Roberts AE ... -  《-》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.

Uludağ Alkaya D ，Lissewski C ，Yeşil G ，Zenker M ，Tüysüz B ... -  《-》

The RASopathies: Biology, genetics and therapeutic options.

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies.

Longo JF ，Carroll SL 《-》