Gene signatures and genotype-phenotype correlations of sensorineural hearing loss in Noonan syndrome and related RASopathies.

Hearing loss frequently occurs in Noonan syndrome and related RASopathies (NS-RAS), with conductive hearing loss being common. However, the genotypic and phenotypic features of sensorineural hearing loss (SNHL) in NS-RAS, as well as genotype-phenotype correlations, remain unknown. Leveraging in-house database for syndromic deafness (N = 1666), we analyzed the genomic landscape and clinical phenotypes of 94 NS-RAS families with genetically confirmed via targeted panel sequencing. In particular, we explored the genetic signature of SNHL in NS-RAS and provided a detailed description of the auditory characteristics of SNHL, including its natural progression and outcomes of audiological rehabilitation. Additionally, molecular modeling and functional assays were conducted to explore how PTPN11 variants with distinct auditory phenotypes affect downstream signaling pathways. Resultantly, eighteen (19.1%) exhibited SNHL, predominantly with PTPN11 (88.9%) and RAF1 (11.1%) variants. Of these patients, the majority exhibited severe-to-profound SNHL with congenital onset, and cochlear implantation yielded favorable auditory outcomes. The remaining patients maintained normal hearing throughout the follow-up periods. The PTPN11 variants linked to SNHL compromise autoinhibition between the N-SH2 and PTP domains or disrupts the interaction between the C-SH2 domain and phosphorylated tyrosine (pTyr), showing a gain-of-function effect on the RAS/ERK cascade. Specifically, those variants associated with high penetrance and severe expressivity significantly enhanced ERK phosphorylation more than the variants associated with low penetrance and milder expressivity. This is the first cohort study on NS-RAS in South Korea, elucidating the gene signatures and phenotypic characteristics of SNHL and suggesting genotype-auditory phenotype correlations that inform clinical practice.