BMJ Publishing Group, Journal of Medical Genetics, 7(58), p. 465-474, 2020
DOI: 10.1136/jmedgenet-2020-106892
Full text: Unavailable
BackgroundGermline variants inPTPN11are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients withPTPN11pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence ofPTPN11-related NSML or NS in patients with congenital SNHL and explored the expression ofPTPN11and the underlying mechanisms in the auditory system.MethodsA total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients withPTPN11variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish withPtpn11knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes.ResultsTen NSML/NS probands were diagnosed via the identification of pathogenic variants ofPTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded byPtpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown ofptpn11aand overexpression of mutantPTPN11were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom inPTPN11-associated NSML or NS. Other features may be mild, especially in children.ConclusionScreening forPTPN11in patients with congenital hearing loss and variant-based diagnoses are recommended.