R.J.E. Pennings

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations

Abstract. Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.

Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment

In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both.

Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss

Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Here we present OTOGL mutations, a homozygous one base pair deletion (c.1430 delT) causing a frameshift (p.Val477Glufs(∗)25) in a large consanguineous family and two compound heterozygous mutations, c.547C>T (p.Arg183(∗)) and c.5238+5G>A, in a nonconsanguineous family with moderate nonsyndromic sensorineural hearing loss. OTOGL maps to the DFNB84 locus at 12q21.31 and encodes otogelin-like, which has structural similarities to the epithelial-secreted mucin protein family. We demonstrate that Otogl is expressed in the inner ear of vertebrates with a transcription level that is high in embryonic, lower in neonatal, and much lower in adult stages. Otogelin-like is localized to the acellular membranes of the cochlea and the vestibular system and to a variety of inner ear cells located underneath these membranes. Knocking down of otogl with morpholinos in zebrafish leads to sensorineural hearing loss and anatomical changes in the inner ear, supporting that otogelin-like is essential for normal inner ear function. We propose that OTOGL mutations affect the production and/or function of acellular structures of the inner ear, which ultimately leads to sensorineural hearing loss.

Giant laryngoceles: a cause of upper airway obstruction

Abstract Laryngoceles and saccular cysts, which are abnormal dilatations of the laryngeal saccule, are uncommon. The etiology is unknown but is probably related to both congenital and acquired factors. These structures are usually asymptomatic and are incidentally discovered through radiographic studies for unrelated symptoms. We describe two patients with upper airway obstruction, one caused by a giant laryngocele and the other by a large saccular cyst. In the former patient, acute tracheotomy had to be performed. The laryngocele and saccular cyst were removed surgically, which relieved patients’ symptoms of upper airway obstruction.

Genotype-Phenotype Correlation in DFNB8/10 Families with TMPRSS3 Mutations

In the present study, genotype–phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation.

Quality of life and cochlear implantation in Usher syndrome type I.

Objectives: The objectives of this descriptive, retrospective study were to evaluate quality of life, hearing, and vision in patients with Usher syndrome type I with and without cochlear implant.

Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S).

Objective: Genotype a family trait with autosomal dominant nonsyndromic sensorineural hearing impairment guided only by the phenotype. Study design: Family study. Setting: Tertiary referral center. Patients: Fifteen family members. Methods: In the first phase, sequence analysis was performed on DNA isolated from buccal swabs of the proband and her daughter, guided by the phenotype based on audiometric data that were already available. After detection of the W276S missense mutation in the KCNQ4 gene in both patients, this finding was confirmed in the other affected family members. All participants completed a questionnaire, were clinically examined, and underwent standard pure-tone audiometry. The results were analyzed to refine the phenotypic features of the family trait. Results: All clinically affected participants were carriers of the W276S hotspot mutation in exon 5 of the KCNQ4 gene on chromosome 1p34. Refined phenotypic features confirmed previously described phenotypes of DFNA2 families. Conclusions: Phenotype determination can be cost saving and very effective in detecting the genotype of autosomal dominant nonsyndromic hearing impairment, especially when phenotype analyses can be performed on data that are already available or easily collected.

Disruption of Teashirt Zinc Finger Homeobox 1 Is Associated with Congenital Aural Atresia in Humans

Congenital aural atresia (CAA) can occur as an isolated congenital malformation or in the context of a number of monogenic and chromosomal syndromes. CAA is frequently seen in individuals with an 18q deletion, which is characterized by intellectual disability, reduced white-matter myelination, foot deformities, and distinctive facial features. Previous work has indicated that a critical region for CAA is located in 18q22.3. We studied four individuals (from two families) with CAA and other features suggestive of an 18q deletion, and we detected overlapping microdeletions in 18q22.3 in both families. The minimal region of deletion overlap (72.9-73.4 Mb) contained only one known gene, TSHZ1, which was recently shown to be important for murine middle-ear development. Sequence analysis of the coding exons in TSHZ1 in a cohort of 11 individuals with isolated, nonsyndromic bilateral CAA revealed two mutations, c.723G>A (p.Trp241X) and c.946_947delinsA (p.Pro316ThrfsX16), and both mutations predicted a loss of function. Together, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency.

Usher syndrome type III can mimic other types of Usher syndrome.

Clinical and genetic characteristics are presented of 2 patients from a Dutch Usher syndrome type III family who have a new homozygous USH3 gene mutation: 149–152delCAGG + insTGTCCAAT. One individual (IV: 1) is profoundly hearing impaired and has normal vestibular function and retinitis punctata albescens (RPA). The other individual is also profoundly hearing impaired, but has well-developed speech, vestibular areflexia, and retinitis pigmentosa sine pigmento (RPSP). These findings suggest that Usher syndrome type III can be clinically misdiagnosed as either Usher type I or II; that Usher syndrome patients who are profoundly hearing impaired and have normal vestibular function should be tested for USH3 mutations; and that RPA and RPSP can occur as fundoscopic manifestations of pigmentary retinopathy in Usher syndrome.

Vestibular deterioration precedes hearing deterioration in the P51S COCH mutation (DFNA9): an analysis in 74 mutation carriers.

Objectives: To analyze cochleovestibular impairment features in P51S COCH mutation carriers (n = 22) in a new, large Dutch family and to compare the results to those obtained in previously identified similar mutation carriers (n = 52). To evaluate age-related features between progressive hearing and vestibular impairment of all mutation carriers (n = 74). Study Design: Family study. Methods: Regression analysis was performed in relation to age to outline the development of hearing thresholds, speech recognition scores, and vestibulo-ocular reflex time constant as the key vestibular response parameter. Results: Pure tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers in the new family were essentially similar to those previously established in all other mutation carriers. Hearing started to deteriorate in all mutation carriers from 43 years of age onwards, whereas deterioration of vestibular function started from age 34. Conclusion: Vestibular impairment starts earlier, progresses more rapidly, and, eventually, is more complete than hearing impairment in P51S COCH mutation carriers.