Clinical and molecular characterization of a RASopathy cohort from Türkiye and an AMMECR1 ‐related noonan syndrome‐mimicking phenotype

Abstract

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.