Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis.

Pathogenic missense variants in COCH are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular dysfunction. This study is a comprehensive overview of genotype-phenotype correlations using the PRISMA and HuGENet guidelines. Study characteristics, risk of bias, genotyping and data on the self-reported age of onset, symptoms of vestibular dysfunction, normative test results for vestibular function, and results of audiovestibular examinations were extracted for each underlying pathogenic COCH variant. The literature search yielded 48 studies describing the audiovestibular phenotypes of 27 DFNA9-associated variants in COCH. Subsequently, meta-analysis of audiometric data was performed by constructing age-related typical audiograms and by performing non-linear regression analyses on the age of onset and progression of hearing loss. Significant differences were found between the calculated ages of onset and progression of the audiovestibular phenotypes of subjects with pathogenic variants affecting either the LCCL domain of cochlin or the vWFA2 and Ivd1 domains. We conclude that the audiovestibular phenotypes associated with DFNA9 are highly variable. Variants affecting the LCCL domain of cochlin generally lead to more progression of hearing loss when compared to variants affecting the other domains. This review serves as a reference for prospective natural history studies in anticipation of mutation-specific therapeutic interventions.

A Novel COCH Mutation Affects the vWFA2 Domain and Leads to a Relatively Mild DFNA9 Phenotype.

OBJECTIVE: To study the genotype and phenotype of a Dutch family with autosomal dominantly inherited hearing loss. STUDY DESIGN: Genotype-phenotype correlation study. Genetic analysis consisted of linkage analysis, variable number of tandem repeats analysis, and Sanger sequencing. Audiovestibular function was examined. Regression analysis was performed on pure tone audiometry and speech recognition scores and correlated with the age and/or level of hearing loss. SETTING: Tertiary referral center. PATIENTS: A large Dutch family presenting with sensorineural hearing loss. MAIN OUTCOME MEASURES: Identification of the underlying genetic defect of the hearing loss in this family. Results of pure tone and speech audiometry, onset age, progression of hearing loss and vestibular (dys)function. RESULTS: A novel mutation in COCH, c.1312C > T p.(Arg438Cys), cosegregates with hearing loss and a variable degree of vestibular (dys)function in this family. The reported mean age of onset of hearing loss is 33 years (range, 18-49 yr). Hearing loss primarily affects higher frequencies and its progression is relatively mild (0.8 dB/yr). Speech perception is remarkably well preserved in affected family members when compared with other DFNA9 families with different COCH mutations. CONCLUSION: These findings expand the genotypic and phenotypic spectrum of DFNA9. The c.1312C > T mutation, which affects the vWFA2 domain, causes a relatively mild audiovestibular phenotype when compared with other COCH mutations.

Hearing Results of Surgery for Acquired Atresia of the External Auditory Canal.

OBJECTIVE: To evaluate short- and long-term hearing results of surgery for acquired atresia of the external auditory canal (EAC) in a large patient cohort and to define preoperative audiometric conditions useful for patient counseling. STUDY DESIGN: Retrospective cohort study. SETTING: Academic tertiary referral center. PATIENTS: Seventy-eight ears from 72 patients with postinflammatory acquired atresia of the EAC who underwent canal- and meatoplasty were included. Patients with involvement of the ossicular chain, (syndromic) external ear malformations, or congenital aural atresia were excluded. INTERVENTION: Canal- and meatoplasty. MAIN OUTCOME MEASURES: Mean pure-tone averages of thresholds at 0.5, 1, 2, and 3 kHz (PTA0.5,1,2,3) for air conduction (AC), bone conduction, and air-bone gap (ABG) were calculated preoperatively and at short-term (≤0.55 yr) and long-term follow-up (>0.55 yr). Additionally, the numbers of ears with a closed ABG ≤10 dB and ≤20 dB, and with Social hearing (defined as: AC PTA0.5,1,2,3 ≤35 dB) were assessed. RESULTS: At short-term follow-up AC PTA0.5,1,2,3 improved by 18 dB. Social hearing was obtained in 81% of the ears. Postoperatively, 35% of the ears had a closed ABG ≤10 dB, 83% was closed ≤20 dB. During follow-up, significant deterioration of 5 to 7 dB occurred for AC thresholds at 0.25, 0.5, and 1 kHz. CONCLUSIONS: Surgery for acquired atresia of the EAC is often beneficial. This study suggests overall advantageous surgery when the preoperative indication criteria ABG PTA0.5,1,2,3 >20 dB and AC PTA0.5,1,2,3 >35 dB are applied.

Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37.

PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing. CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.

A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa.

OBJECTIVES: Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. DESIGN: A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups. RESULTS: Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations. CONCLUSIONS: The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions.

Audioprofile Surfaces: The 21st Century Audiogram.

OBJECTIVE: To present audiometric data in 3 dimensions by considering age as an addition dimension. METHODS: Audioprofile surfaces (APSs) were fitted to a set of audiograms by plotting each measurement of an audiogram as an independent point in 3 dimensions with the x, y, and z axes representing frequency, hearing loss in dB, and age, respectively. RESULTS: Using the Java-based APS viewer as a standalone application, APSs were pre-computed for 34 loci. By selecting APSs for the appropriate genetic locus, a clinician can compare this APS-generated average surface to a specific patient's audiogram. CONCLUSION: Audioprofile surfaces provide an easily interpreted visual representation of a person's hearing acuity relative to others with the same genetic cause of hearing loss. Audioprofile surfaces will support the generation and testing of sophisticated hypotheses to further refine our understanding of the biology of hearing.

Audiometric Characteristics of a Dutch DFNA10 Family With Mid-Frequency Hearing Impairment.

OBJECTIVES: Mutations in EYA4 can cause nonsyndromic autosomal dominant sensorineural hearing impairment (DFNA10) or a syndromic variant with hearing impairment and dilated cardiomyopathy. A mutation in EYA4 was found in a Dutch family, causing DFNA10. This study is focused on characterizing the hearing impairment in this family. DESIGN: Whole exome sequencing was performed in the proband. In addition, peripheral blood samples were collected from 23 family members, and segregation analyses were performed. All participants underwent otorhinolaryngological examinations and pure-tone audiometry, and 12 participants underwent speech audiometry. In addition, an extended set of audiometric measurements was performed in five family members to evaluate the functional status of the cochlea. Vestibular testing was performed in three family members. Two individuals underwent echocardiography to evaluate the nonsyndromic phenotype. RESULTS: The authors present a Dutch family with a truncating mutation in EYA4 causing a mid-frequency hearing impairment. This mutation (c.464del) leads to a frameshift and a premature stop codon (p.Pro155fsX). This mutation is the most N-terminal mutation in EYA4 found to date. In addition, a missense mutation, predicted to be deleterious, was found in EYA4 in two family members. Echocardiography in two family members revealed no signs of dilated cardiomyopathy. Results of caloric and velocity step tests in three family members showed no abnormalities. Hearing impairment was found to be symmetric and progressive, beginning as a mid-frequency hearing impairment in childhood and developing into a high-frequency, moderate hearing impairment later in life. Furthermore, an extended set of audiometric measurements was performed in five family members. The results were comparable to those obtained in patients with other sensory types of hearing impairments, such as patients with Usher syndrome type IIA and presbyacusis, and not to those obtained in patients with (cochlear) conductive types of hearing impairment, such as DFNA8/12 and DFNA13. CONCLUSIONS: The mid-frequency hearing impairment in the present family was found to be symmetric and progressive, with a predominantly childhood onset. The results of psychophysical measurements revealed similarities to other conditions involving a sensory type of hearing impairment, such as Usher syndrome type IIA and presbyacusis. The study results suggest that EYA4 is expressed in the sensory cells of the cochlea. This phenotypic description will facilitate counseling for hearing impairment in DFNA10 patients.

Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease.

OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations. DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations. RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression. CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice.

Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.

Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.

OBJECTIVE: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox). STUDY DESIGN: Double-blind follow-up study. SETTING: University hospital. PATIENTS: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years. INTERVENTION: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level. MAIN OUTCOME MEASURES: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment. RESULTS: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups. CONCLUSION: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

Intrafamilial variable hearing loss in TRPV4 induced spinal muscular atrophy.

OBJECTIVE: Mutations in the transient receptor potential vanilloid 4 gene (TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular atrophy caused by a mutation in TRPV4. METHODS: A neurological examination was repeated and pure tone and speech audiometry were performed. RESULTS: A large variety in neurological symptoms as well as variation in audiometric characteristics was observed. The severity of hearing loss is mild to moderate and the audiogram configuration is highly variable. The hearing loss of these patients has a progressive nature in general. The frequencies that deteriorate significantly differ between family members. When compared to presbyacusis patients, speech recognition scores of patients with a TRPV4 mutation are not clearly different. CONCLUSION: The function of TRPV4 in the inner ear is still elusive but it is suggested that TRPV4 is required for maintenance of cochlear function in stress conditions, like acoustic injury. We can neither confirm nor reject this based on the results obtained in this family. Therefore, one might consider advising patients with a TRPV4 mutation to avoid exposure to environmental influences such as noise exposure.

Similar phenotypes caused by mutations in OTOG and OTOGL.

OBJECTIVES: Recently, OTOG and OTOGL were identified as human deafness genes. Currently, only four families are known to have autosomal recessive hearing loss based on mutations in these genes. Because the two genes code for proteins (otogelin and otogelin-like) that are strikingly similar in structure and localization in the inner ear, this study is focused on characterizing and comparing the hearing loss caused by mutations in these genes. DESIGN: To evaluate this type of hearing, an extensive set of audiometric and vestibular examinations was performed in the 13 patients from four families. RESULTS: All families show a flat to downsloping configuration of the audiogram with mild to moderate sensorineural hearing loss. Speech recognition scores remain good (>90%). Hearing loss is not significantly different in the four families and the psychophysical test results also do not differ among the families. Vestibular examinations show evidence for vestibular hyporeflexia. CONCLUSION: Because otogelin and otogelin-like are localized in the tectorial membrane, one could expect a cochlear conductive hearing loss, as was previously shown in DFNA13 (COL11A2) and DFNA8/12 (TECTA) patients. Results of psychophysical examinations, however, do not support this. Furthermore, the authors conclude that there are no phenotypic differences between hearing loss based on mutations in OTOG or OTOGL. This phenotype description will facilitate counseling of hearing loss caused by defects in either of these two genes.

Familial aggregation of pure tone hearing thresholds in an aging European population.

OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated. STUDY DESIGN: Multicenter survey in 8 European centers. SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study. RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies. DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.

AudioGene: predicting hearing loss genotypes from phenotypes to guide genetic screening.

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a common and often progressive sensory deficit. ADNSHL displays a high degree of genetic heterogeneity and varying rates of progression. Accurate, comprehensive, and cost-effective genetic testing facilitates genetic counseling and provides valuable prognostic information to affected individuals. In this article, we describe the algorithm underlying AudioGene, a software system employing machine-learning techniques that utilizes phenotypic information derived from audiograms to predict the genetic cause of hearing loss in persons segregating ADNSHL. Our data show that AudioGene has an accuracy of 68% in predicting the causative gene within its top three predictions, as compared with 44% for a majority classifier. We also show that AudioGene remains effective for audiograms with high levels of clinical measurement noise. We identify audiometric outliers for each genetic locus and hypothesize that outliers may reflect modifying genetic effects. As personalized genomic medicine becomes more common, AudioGene will be increasingly useful as a phenotypic filter to assess pathogenicity of variants identified by massively parallel sequencing.

Clinical follow-up and histopathology of the temporal bones in Nathalie syndrome.

The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy.

Optokinetic response in patients with vestibular areflexia.

Optokinetic nystagmus (OKN) responses (stimuli 40°/s and 60°/s) were evaluated in 121 patients with vestibular areflexia (VA) and were compared with a control group of 99 control subjects matched by age. The mean response levels were significantly higher in the VA group than in the control group: 1.7°/s at 40°/s stimulation, and 4.4°/s at 60°/s. The VA group showed a significantly wider scattering and greater variances and, as a group, they exhibited higher OKN gains than the control subjects. We suggest that the higher gain of OKN responses in VA patients can be attributed to an increased efficiency in signal processing by the cortical optokinetic system. This enhancement may be similar to the enhancement which, in healthy subjects, is produced by "optokinetic training".

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.

Phenotype analysis of an Australian DFNA9 family with the 1109N COCH mutation.

OBJECTIVES: We studied the clinical characteristics of an Australian family with an autosomal dominant sensorineural hearing impairment (DFNA9) caused by an I109N mutation in COCH. METHODS: Retrospective analyses of audiometric data from 8 mutation carriers of an Australian DFNA9 family with the I109N COCH mutation were performed. Cross-sectional hearing levels related to age, age-related typical audiograms, and speech recognition scores related to age and to the level of hearing impairment were investigated. Data were compared to those obtained in previously identified DFNA9 families with P51S, V66G, G87W, G88E, I109T, and C542F COCH mutations. RESULTS: Deterioration of hearing in the I109N mutation carriers started before the age of 40 years. The audiometric characteristics of the I109N mutation carriers are essentially similar to those previously established in I109T mutation carriers and, to a lesser extent, in P51S, G87W, and G88E mutation carriers. CONCLUSIONS: The phenotype associated with the I109N COCH mutation is largely similar to that associated with the I109T, P51S, G87W, and G88E mutation carriers. However, subtle differences seem to exist in terms of age of onset and rate of progression.

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.