Novel Variants in PTPN11 , NF1 , RASA2 , and MAP2K1 : Expanding the Molecular Spectrum of RASopathies in a Turkish...

Area of Science:

• Genetics and Developmental Biology
• Molecular Signaling Pathways
• Clinical Genetics

Background:

• RASopathies are a group of genetically diverse developmental disorders.
• These conditions arise from germline variants in the RAS/MAPK signaling pathway.
• They present with overlapping clinical features and varied molecular causes.

Purpose of the Study:

• To investigate the clinical and molecular spectrum of RASopathies.
• To identify novel and rare genetic variants associated with these disorders.
• To explore genotype-phenotype correlations in a patient cohort.

Main Methods:

• A retrospective, multicenter study involving 23 patients with suspected RASopathy.
• Diagnosis confirmed through targeted Next Generation Sequencing (NGS) analysis.
• Variants classified using American College of Medical Genetics (ACMG) criteria; clinical data reviewed.

Main Results:

• Noonan syndrome (65.2%), Neurofibromatosis Type 1 (21.7%), Cardio-facio-cutaneous syndrome (8.7%), and NF-Noonan syndrome (4.3%) were diagnosed.
• Common findings included craniofacial dysmorphism (91.3%), musculoskeletal anomalies (82.6%), and cutaneous features (78.3%).
• Twenty-four heterozygous variants were found in seven genes, with PTPN11 and NF1 being most frequent. Four novel variants were identified in PTPN11, RASA2, NF1, and MAP2K1.

Conclusions:

• RASopathies exhibit significant clinical and molecular heterogeneity.
• Novel variants, including those in RASA2, expand the known spectrum of RASopathy-associated alterations.
• Comprehensive NGS testing is crucial for diagnosis, guiding individualized, multidisciplinary patient care.