Background Germline variants in PTPN11 are 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 with PTPN11 pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence of PTPN11-related NSML or NS in patients with congenital SNHL and explored the expression of PTPN11 and the underlying mechanisms in the auditory system.
Methods A total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients with PTPN11 variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish with Ptpn11 knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes.
Results Ten NSML/NS probands were diagnosed via the identification of pathogenic variants of PTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded by Ptpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown of ptpn11a and overexpression of mutant PTPN11 were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom in PTPN11-associated NSML or NS. Other features may be mild, especially in children.
Conclusion Screening for PTPN11 in patients with congenital hearing loss and variant-based diagnoses are recommended.
- clinical genetics
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XG and S-SH contributed equally.
PD and Y-YY contributed equally.
Contributors Y-YY, PD and XG participated in the design of the study and drafted the manuscript. S-SH and DK participated in data collection and data analysis. S-WQ, W-QW, YS, J-CX and H-YX participated in the in vivo and in vitro experiments. All authors read and approved the final manuscript.
Funding This work was supported by grants from National key R&D project (2016YFC1000706, 2016YFC1000704), National Natural Science Foundation of China (81730029, 81873704, 81870731, 81570929 and 61827805), Beijing Natural Science Foundation (7191011, 7192234) and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund (2017-JQPY-001).
Disclaimer The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval This study was approved by the Chinese People’s Liberation Army General Hospital Research Ethics Committee (reference number S2016–120–02). The authors obtained fully informed written consent from adult subjects and parents of minor subjects for participation and publication of their clinical data. All in vivo experiments were carried out in accordance with CALAS (Chinese Association for Laboratory Animal Science) guidelines for the care and use of laboratory animals and were approved by the Animal Care and Use Committees of the Chinese PLA General Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. The patient’s phenotype and the detected variants have been submitted to the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and the accession numbers are from SCV000992390 to SCV000992419.
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