Abstract
X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gusher upon stapedectomy or cochleostomy. The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.
Highlights
X-linked deafness, which accounts for approx. 5% of all cases of congenital deafness, is categorized into seven types according to age of onset and hearing phenotype [1]
Six variants of POU3F4 were identified in this cohort by next-generation sequencing (NGS)
High-resolution computed tomography (CT) showed that the basal turn of the cochlea was incompletely separated from the dilated internal auditory canal, along with an absence of the modiolus and interscalar septum; this condition was designated as cochlear incomplete partition type III (IP-III) [4]
Summary
X-linked deafness, which accounts for approx. 5% of all cases of congenital deafness, is categorized into seven types according to age of onset and hearing phenotype [1]. Five X-linked genes have been found to be related to the etiology of non-syndromic hearing loss (NSHL): PRPS1 (DFNX1, OMIM: 311850), POU3F4 (DFNX2, OMIM: 300039), SMPX (DFNX4, OMIM: 300226), AIFM1 (DFNX5, OMIM: 300169) and COL4A6 (DFNX6, OMIM: 303631). Among these causative mutant genes for syndromic hearing loss (SHL), GPRASP2 (DFNX7, OMIM: 300969) was shown to be associated with X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, while COL4A5 (OMIM: 301050) was implicated in Alport syndrome (OMIM: 301050) and TIMM8A (OMIM: 300356) in deafness-dystonia-optic neuropathy syndrome (Mohr–Tranebjærg syndrome OMIM: 304700). High-resolution computed tomography (CT) showed that the basal turn of the cochlea was incompletely separated from the dilated internal auditory canal (internal auditory meatus; IAM), along with an absence of the modiolus and interscalar septum; this condition was designated as cochlear incomplete partition type III (IP-III) [4]
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