Öz

Objective: Noonan syndrome (NS) and related RASopathies are genetically heterogeneous disorders caused by dysregulation of the RAS/MAPK signaling pathway and are characterized by overlapping clinical features, including distinctive craniofacial appearance, growth impairment, congenital heart defects (CHD), and variable neurodevelopmental involvement. Comprehensive molecular characterization is essential for accurate diagnosis and genotype–phenotype correlation. Evaluation of well-characterized single-center pediatric cohorts may provide clinically relevant real-world insight into genotype–phenotype relationships within routine practice. The aim of this study is to delineate genotype–phenotype correlations in a well-characterized pediatric cohort.

Materials and Methods: This retrospective single-center study included pediatric patients between January 2022 and September 2025 with molecularly confirmed diagnosis of NS and related RASopathies. Clinical, laboratory, and imaging findings were reviewed. Targeted next-generation sequencing of RASopathy-associated genes was performed. Detected variants were interpreted according to American College of Medical Genetics and Genomics guidelines, and segregation analysis was conducted when available.

Results: The cohort comprised 20 pediatric patients from 19 unrelated families, with a mean age of 6.1 years. CHD was identified in 80% of patients, most commonly pulmonary valve stenosis (65%), while cardiac involvement was not universal. Short stature was observed in 65% of cases and represented the most frequent reason for referral. Disease-associated variants were identified in nine different genes, with PTPN11 being the most frequently affected (40%), followed by LZTR1 (15%), NF1 (10%), and RAF1
(10%). Most variants were classified as pathogenic or likely pathogenic, whereas a limited number were categorized as variants of uncertain significance. Integrated interpretation incorporating phenotype–genotype concordance and segregation data supported the potential clinical relevance of selected uncertain variants.

Conclusion: This pediatric cohort highlights the marked clinical and genetic heterogeneity of NS and related RASopathies. The absence of cardiac involvement in some patients underscores the limitations of phenotype-based assessment alone. Comprehensive molecular testing remains critical for accurate diagnosis, refinement of genotype–phenotype correlations, and appropriate long-term management.

Anahtar Kelimeler: Genotype–phenotype correlation, genetic testing, MAP kinase signaling system, next-generation sequencing, noonan syndrome, rasopathies

Kaynakça

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Nasıl atıf yapılır

1.
Sanrı A, Kontbay Cetin T, Usta E, Mutlu MB, Sezer O, Sanri E. Pediatrik bir kohortta RASopatilerin klinik ve moleküler spektrumu: Tek merkezli retrospektif bir çalışma. Turk J Pediatr Dis. 2026;Early View:1-8. https://doi.org/10.12956/TJPD.2025.1301