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. 2024 Sep 13;19(1):342.
doi: 10.1186/s13023-024-03338-z.

Genomic and phenotypic landscapes of X-linked hereditary hearing loss in the Chinese population

Haifeng Feng #  1   2   3   4   5   6 , Shasha Huang #  1   2   3   4   5 , Ying Ma  1   2   3   4   5 , Jinyuan Yang  1   2   3   4   5 , Yijin Chen  1   2   3   4   5 , Guojian Wang  1   2   3   4   5 , Mingyu Han  1   2   3   4   5 , Dongyang Kang  1   2   3   4   5 , Xin Zhang  1   2   3   4   5 , Pu Dai  7   8   9   10   11 , Yongyi Yuan  12   13   14   15   16
Affiliations

Genomic and phenotypic landscapes of X-linked hereditary hearing loss in the Chinese population

Haifeng Feng et al. Orphanet J Rare Dis. .

Abstract

Background: Hearing loss (HL) is the most common sensory birth deficit worldwide, with causative variants in more than 150 genes. However, the etiological contribution and clinical manifestations of X-linked inheritance in HL remain unclear within the Chinese HL population. In this study, we focused on X-linked hereditary HL and aimed to assess its contribution to hereditary HL and identify the genotype-phenotype relationship.

Methods: We performed a molecular epidemiological investigation of X-linked hereditary HL based on next-generation sequencing and third-generation sequencing in 3646 unrelated patients with HL. We also discussed the clinical features associated with X-linked non-syndromic HL-related genes based on a review of the literature.

Results: We obtained a diagnostic rate of 52.72% (1922/3646) among our patients; the aggregate contribution of HL caused by genes on the X chromosome in this cohort was ~ 1.14% (22/1922), and POU3F4 variants caused ~ 59% (13/22) of these cases. We found that X-linked HL was congenital or began during childhood in all cases, with representative audiological profiles or typical cochlear malformations in certain genes. Genotypic and phenotypic analyses showed that causative variants in PRPS1 and AIFM1 were mainly of the missense type, suggesting that phenotypic variability was correlated with the different effects that the replaced residues exert on structure and function. Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy. No phenotypic differences were identified in patients carrying POU3F4 or COL4A6 variants.

Conclusions: Our work constitutes a preliminary evaluation of the molecular contribution of X-linked genes in heritable HL (~ 1.14%). The 15 novel variants reported here expand the mutational spectrum of these genes. Analysis of the genotype-phenotype relationship is valuable for X-linked HL precise diagnostics and genetic counseling. Elucidation of the pathogenic mechanisms and audiological profiles of HL can also guide choices regarding treatment modalities.

Keywords: DFNX; Genetic variants spectrum; Genotype–phenotype correlations; X-linked hearing loss.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Deafness-related genes on the X chromosome. A Graphical representation of diseases and loci associated to syndromic (right side) and non-syndromic (left side) forms of X-linked HL. B X-linked genes and their proportions identified in the Chinese HL population
Fig. 2
Fig. 2
Pedigrees and audiometric characteristics of patients with SMPX variants. A Pedigrees of two deaf probands harboring SMPX variants; B audiogram of patient 1-II-1 and 2-IV-2; C representative audiograms (air conduction) of affected men at different ages
Fig. 3
Fig. 3
The variant and disease spectra of DFNX genes. A PRPS1 variants and associated diseases; B the variant spectrum of POU3F4 gene; C SMPX variants cause X-linked NSHL or adult-onset distal myopathy. D AIFM1 variations in auditory neuropathy as well as syndromes. #: The variants were reported in this study
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