Dataset Information

A New Pathogenic Variant in POU3F4 Causing Deafness Due to an Incomplete Partition of the Cochlea Paved the Way for Innovative Surgery.

ABSTRACT: Incomplete partition type III (IP-III) is a relatively rare inner ear malformation that has been associated with a POU3F4 gene mutation. The IP-III anomaly is mainly characterized by incomplete separation of the modiolus of the cochlea from the internal auditory canal. We describe a 71-year-old woman with profound sensorineural hearing loss diagnosed with an IP-III of the cochlea that underwent cochlear implantation. Via targeted sequencing with a non-syndromic gene panel, we identified a heterozygous c.934G > C p. (Ala31Pro) pathogenic variant in the POU3F4 gene that has not been reported previously. IP-III of the cochlea is challenging for cochlear implant surgery for two main reasons: liquor cerebrospinalis gusher and electrode misplacement. Surgically, it may be better to opt for a shorter array because it is less likely for misplacement with the electrode in a false route. Secondly, the surgeon has to consider the insertion angles of cochlear access very strictly to avoid misplacement along the inner ear canal. Genetic results in well describes genotype-phenotype correlations are a strong clinical tool and as in this case guided surgical planning and robotic execution.

SUBMITTER: Tekin AM

PROVIDER: S-EPMC8143104 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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A New Pathogenic Variant in <i>POU3F4</i> Causing Deafness Due to an Incomplete Partition of the Cochlea Paved the Way for Innovative Surgery.

Tekin Ahmet M AM Matulic Marco M Wuyts Wim W Assadi Masoud Zoka MZ Mertens Griet G Rompaey Vincent van VV Li Yongxin Y Heyning Paul van de PV Topsakal Vedat V

Genes 20210421 5

Incomplete partition type III (IP-III) is a relatively rare inner ear malformation that has been associated with a <i>POU3F4</i> gene mutation. The IP-III anomaly is mainly characterized by incomplete separation of the modiolus of the cochlea from the internal auditory canal. We describe a 71-year-old woman with profound sensorineural hearing loss diagnosed with an IP-III of the cochlea that underwent cochlear implantation. Via targeted sequencing with a non-syndromic gene panel, we identified a ...[more]

PMID: 33919129

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Project description:Pathogenic variants in the SLC26A4, FOXI1, and KCNJ10 genes are associated with hearing loss (HL) and specific inner ear abnormalities (DFNB4). In the present study, phenotype analyses, including clinical data collection, computed tomography (CT), and audiometric examination, were performed on deaf individuals from the Sakha Republic of Russia (Eastern Siberia). In cases with cochleovestibular malformations, molecular genetic analysis of the coding regions of the SLC26A4, FOXI1, and KCNJ10 genes associated with DFNB4 was completed. In six of the 165 patients (3.6%), CT scans revealed an incomplete partition of the cochlea (IP-1 and IP-2), in isolation or combined with an enlarged vestibular aqueduct (EVA) anomaly. Sequencing of the SLC26A4, FOXI1, and KCNJ10 genes was performed in these six patients. In the SLC26A4 gene, we identified four variants, namely c.85G>C p.(Glu29Gln), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln), and c.2089+1G>A (IVS18+1G>A), which are known as pathogenic, as well as c.441G>A p.(Met147Ile), reported previously as a variant with uncertain significance. Using the AlphaFold algorithm, we found in silico evidence of the pathogenicity of this variant. We did not find any causative variants in the FOXI1 and KCNJ10 genes, nor did we find any evidence of digenic inheritance associated with double heterozygosity for these genes with monoallelic SLC26A4 variants. The contribution of biallelic SLC26A4 variants in patients with IP-1, IP-2, IP-2+EVA, and isolated EVA was 66.7% (DFNB4 in three patients, Pendred syndrome in one patient). Seventy-five percent of SLC26A4-biallelic patients had severe or profound HL. The morphology of the inner ear anomalies demonstrated that, among SLC26A4-biallelic patients, all types of incomplete partition of the cochlea are possible, from IP-1 and IP-2, to a normal cochlea. However, the dominant type of anomaly was IP-2+EVA (50.0%). This finding is very important for cochlear implantation, since the IP-2 anomaly does not have an increased risk of “gushers” and recurrent meningitis.

Project description:ObjectiveIncomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms.Material and methodsTen 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene.ResultsMutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their child's psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms.ConclusionsWhile cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an extensive and consistent multidisciplinary team approach during childhood to support their overall habilitation.

Dataset Information

A New Pathogenic Variant in POU3F4 Causing Deafness Due to an Incomplete Partition of the Cochlea Paved the Way for Innovative Surgery.

Publications

A New Pathogenic Variant in <i>POU3F4</i> Causing Deafness Due to an Incomplete Partition of the Cochlea Paved the Way for Innovative Surgery.

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