Abstract
BackgroundPOU3F4 is the causative gene for X-linked deafness-2 (DFNX2), characterized by incomplete partition type III (IP-III) malformation of the inner ear. The purpose of this study was to investigate the clinical characteristics and molecular findings in IP-III patients by Sanger or nanopore single-molecule sequencing.MethodsDiagnosis of IP-III was mainly based on clinical characteristics including radiological and audiological findings. Sanger sequencing of POU3F4 was carried out for these IP-III patients. For those patients with negative results for POU3F4 Sanger sequencing, nanopore long-read single-molecule sequencing was used to identify the possible pathogenic variants. Hearing intervention outcomes of hearing aids (HAs) fitting and cochlear implantation (CI) were also analyzed. Aided pure tone average (PTA) was further compared between two groups of patients according to their different locations of POU3F4 variants: in the exon region or in the upstream region.ResultsIn total, 18 male patients from 14 unrelated families were diagnosed with IP-III. 10 variants were identified in POU3F4 by Sanger sequencing and 6 of these were reported for the first time (p.Gln181*, p.Val215Gly, p.Arg282Gln, p.Gln316*, c.903_912 delins TGCCA and p.Arg205del). Four different deletions that varied from 80 to 486 kb were identified 876–1503 kb upstream of POU3F4 by nanopore long-read single-molecule sequencing. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutations. Among these 18 patients, 7 had bilateral HAs and 10 patients received unilateral CI. The mean aided PTA for HAs and CI users were 41.1 ± 5.18 and 40.3 ± 7.59 dB HL respectively. The mean PTAs for patients with the variants located in the exon and upstream regions were 39.6 ± 6.31 versus 43.0 ± 7.10 dB HL, which presented no significant difference (p = 0.342).ConclusionsAmong 14 unrelated IP-III patients, 28.6% (4/14) had no definite mutation in exon region of POU3F4. However, possible pathogenic deletions were identified in upstream region of this gene. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutation. There was no significant difference of hearing intervention outcomes between the IP-III patients with variants located in the exon region and in the upstream region.
Highlights
Hearing loss is the most common sensory deficit with a prevalence of 1–2‰ in newborns [1], while genetic factors have been found to account for over 50% of cases [2]
Chen et al Orphanet Journal of Rare Diseases (2022) 17:65 intervention outcomes between the incomplete partition type III (IP-III) patients with variants located in the exon region and in the upstream region
We report the clinical characteristics and molecular findings in IP-III patients by Sanger or nanopore single-molecule sequencing resulting from POU3F4 anomalies as well as their hearing intervention outcomes
Summary
Hearing loss is the most common sensory deficit with a prevalence of 1–2‰ in newborns [1], while genetic factors have been found to account for over 50% of cases [2]. With respect to genetic hearing loss, deafness is transmitted by an X-linked inheritance pattern in 2–3% of cases [2, 3]. POU3F4, encoding a transcription factor that belongs to the POU-domain family (NM_000307.4) is the most common gene for DFNX is [4, 5]. Previous studies have identified over 90 mutations of POU3F4 related to DFNX2 including missense/nonsense, insertions, deletions, or duplications (The Human Gene Mutation Database, http://www.hgmd.cf.ac.uk). Missense mutations in functional domains might change their structures, and would further disrupt the protein functionssuch as inducing endoplasmic reticulum stress [4, 15,16,17]. POU3F4 is the causative gene for X-linked deafness-2 (DFNX2), characterized by incomplete partition type III (IP-III) malformation of the inner ear. The purpose of this study was to investigate the clinical characteristics and molecular findings in IP-III patients by Sanger or nanopore single-molecule sequencing
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