PUBLICATION

Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms

Authors
Gao, X., Huang, S.S., Qiu, S.W., Su, Y., Wang, W.Q., Xu, H.Y., Xu, J.C., Kang, D.Y., Dai, P., Yuan, Y.Y.
ID
ZDB-PUB-200802-4
Date
2020
Source
Journal of Medical Genetics   58(7): 465-474 (Journal)
Registered Authors
Keywords
clinical genetics, diagnosis
MeSH Terms
  • Incidence
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
  • Male
  • Zebrafish
  • Infant
  • Child
  • Female
  • Asian People/genetics
  • Signal Transduction
  • Cohort Studies
  • Noonan Syndrome/genetics*
  • Mice
  • Gene Knockdown Techniques
  • Adolescent
  • Wnt Proteins/metabolism
  • beta Catenin/metabolism
  • Animals
  • Child, Preschool
  • Humans
  • Hearing Loss, Sensorineural/complications
  • Hearing Loss, Sensorineural/congenital*
  • Hearing Loss, Sensorineural/epidemiology
(all 23)
PubMed
32737134 Full text @ J. Med. Genet.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
WT + MO4-ptpn11astandard conditionsDay 5
1 - 10 of 17
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
s356tTgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    Noonan syndromeTAS
    Noonan syndrome with multiple lentiginesTAS
    1 - 2 of 2
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    Sequence Targeting Reagents
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    GFPEFGGFP
    1 - 1 of 1
    Show
    Mapping
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    Citation
    Gao, X., Huang, S.S., Qiu, S.W., Su, Y., Wang, W.Q., Xu, H.Y., Xu, J.C., Kang, D.Y., Dai, P., Yuan, Y.Y. (2020) Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms. Journal of Medical Genetics. 58(7):465-474.