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RASopathies comprise a group of congenital malformation syndromes with predominant neuro-cardio-facial-cutaneous involvement resulting from pathogenic variants in RAS/mitogen-activated protein kinase (MAPK) signaling pathway genes. In this study 33 patients are presented with their clinical and molecular findings as an RASopathy cohort including a family with an AMMECR1-related disorder. The diagnostic distribution of the cohort included Noonan syndrome (n = 18), neurofibromatosis type 1 (n = 8), and single cases of cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis-Noonan syndrome, NF1 microdeletion syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines and AMMECR1-related midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MIM# 300990). The most prevalent clinical manifestations were dermatological findings (90.9%), skeletal features (84.4%), cardiovascular involvement (75.8%), and typical craniofacial dysmorphism suggestive of RASopathy (72.7%). Variants were most frequently identified in PTPN11 and NF1, followed by single cases involving the BRAF, HRAS, LZTR1, RAF1, RIT1, SHOC2, and SOS1. Notably, one patient harbored a variant in AMMECR1, which is not involved in the RAS/MAPK pathway. Overall, this study delineates the clinical and molecular landscape of a cohort from Türkiye and underscores that the AMMECR1-related phenotype represents a distinct entity that closely mimics Noonan syndrome.

RASopathies are a group of developmental disorders caused by variations in genes of the RAS/mitogen activated protein kinase (MAPK) pathway and affect 1 in 1000 individuals worldwide. Due to overlapping clinical features, accurate diagnosis is challenging and therefore we used next-generation sequencing (NGS) panels as an effective molecular diagnostic tool. Targeted sequencing was performed on 130 samples using a multigene panel comprising of 21 RASopathy genes. Molecular analysis revealed variations in 74 individuals (57%). Pathogenic or likely pathogenic variations were observed in 60/74 (81%) of the cases, 13 (17.5%) had variant(s) of uncertain significance (VUS), and one novel variant was identified in RASA2 whose pathogenicity has not yet been established. In individuals with Noonan Syndrome, pathogenic variants were identified in eight different genes mainly PTPN11, SOS1, RAF1 and LZTR1. Nine clinically diagnosed Cardio-facio-cutaneous syndrome cases harboured variations in BRAF, MAP2K2 and MAP2K1 The c.34G>A variant in HRAS was seen in all nine individuals diagnosed with Costello syndrome. This study provides a comprehensive molecular and clinical profile of the largest Indian RASopathy cohort. The use of targeted gene panel has increased the variation detection rate in affected individuals.

RASopathies are clinically and genetically heterogeneous disorders resulting from dysregulation of the RAS/MAPK pathway. We present a single-center retrospective cohort of 118 genotype-confirmed pediatric patients diagnosed with RASopathy. Noonan syndrome was the most common clinical diagnosis, followed by NF-Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. The most frequent clinical features included short stature, pulmonary stenosis, pectus deformities, and neurocognitive delay. Through molecular analysis, we identified distinct variants across major RAS/MAPK pathway genes, with a considerable proportion of patients carrying rare or less frequently reported variants, including those in LZTR1, RIT1, RAF1, HRAS, BRAF, RASA2, KRAS, CBL, SHOC2, and MAP2K2. In addition to well-established genotype-phenotype correlations, we report several uncommon or previously unrecognized features: microcephaly in multiple PTPN11-positive patients and renal agenesis in a child with a novel HRAS variant diagnosed with Costello syndrome. Furthermore, we identified three patients harboring RASA2 variants, providing additional support for its emerging role in Noonan syndrome. This study expands the clinical and molecular spectrum of pediatric RASopathies. It emphasizes the need for comprehensive genetic evaluation and regular follow-up in the context of overlapping clinical features, supporting accurate diagnosis and identifying candidates for emerging targeted therapies.

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as transforming growth factor-β-activated kinase 1 (TAK1), is a widely expressed kinase that plays a crucial role in various cellular processes variants in the MAP3K7 gene have been implicated in two distinct genetic disorders: frontometaphyseal dysplasia Type 2 (FMD2) and cardiofaciocutaneous syndrome (CSCF). To elucidate the consequences of the MAP3K7 variant, we investigated a Chinese family with CSCF harboring a novel heterozygous MAP3K7 variant and examined the genotype-phenotype correlation. Functional validation was performed using clinical evaluations, whole-exome sequencing (WES), and biochemical assays, including western blotting to assess TAK1 phosphorylation levels and downstream signaling pathways. Clinical data and genomic DNA were collected from the proband and family members. WES identified a novel heterozygous variant in MAP3K7 (NM_145331.3: c.149 T > C, p.Val50Ala) inherited from the affected mother. Sequence conservation analysis revealed that the Val50 residue is highly conserved among vertebrates and is critical for ATP binding. Protein 3D modeling predicted that the Val50Ala variant disrupts the kinase domain structure, potentially impairing TAK1 function. In vitro overexpression experiments in human embryonic kidney 293T (HEK293T) cells demonstrated that the Val50Ala variant significantly reduced TAK1 phosphorylation levels. Furthermore, this variant differentially affected downstream signaling molecules (p38, p65, and JNK) compared with variants causing FMD2. Notably, stimulation with transforming growth factor-β (TGF-β) partially restored the altered phosphorylation patterns, suggesting a potential compensatory mechanism. Our study provides novel insights into the molecular pathogenesis of MAP3K7 variants associated with CSCF and FMD2. We demonstrate that the p.Val50Ala variant impairs TAK1 kinase activity and differentially affects downstream signaling pathways. These findings highlight the distinct molecular fingerprints of MAP3K7 variants causing CSCF versus FMD2 and underscore the importance of considering MAP3K7 variants in the differential diagnosis of syndromic congenital cardiac defects, recurrent infections, and global developmental delays. Our results also suggest that TGF-β signaling may offer a potential therapeutic target for modulating the effects of MAP3K7 variants.