Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.

/pdf/expert-specification-of-the-acmg-amp-variant-interpretation-1fgkgabdoq.pdf

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

The two most common vestibular disorders are motion sickness and vestibular migraine, affecting 30 and 1-2% of the population respectively. Both are related to migraine and show a familial trend. Bilateral vestibular hypofunction is a rare condition, and some of patients also present cerebellar ataxia and neuropathy. We present recent advances in the genetics of vestibular disorders with familial aggregation. The clinical heterogeneity observed in different relatives of the same families suggests a variable penetrance and the interaction of several genes in each family. Some Mendelian sensorineural hearing loss also exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. However, the most relevant finding during the past years is the familial clustering observed in Meniere's disease. By using whole exome sequencing and combining bioinformatics tools, novel variants in DTNA and FAM136A genes have been identified in familial Meniere's disease, and this genomic strategy will facilitate the discovery of the genetic basis of familial vestibular disorders.

/pdf/genetics-of-vestibular-disorders-pathophysiological-insights-4bbo55q404.pdf

Genetics of vestibular disorders: pathophysiological insights

Slc4a11 Gene Disruption in Mice CELLULAR TARGETS OF SENSORINEURONAL ABNORMALITIES

To the Editor:

The prevalence of significant hearing loss (≥ 25 db HL) is 15-20% in young adults and rises to approximately 50% in individuals 80 years of age or older [Morton 1991]. Autosomal dominant nonsyndromic hearing loss (ADSNHL) accounts for approximately 15% of inherited hearing loss. To date, 22 genes have been implicated as causative for ADNSHL, and a further 30 loci mapped to autosomal chromosomal regions [Van Camp and Smith 2007].

ADSNHL at the DFNA9 locus is unusual amongst ADNSHL forms of deafness in that it is also associated with vestibular dysfunction. This type of hearing loss is caused by mutations in the COCH gene (chromosome 14q12), which encodes cochlin, a protein that consists of a signal peptide, an LCCL module, and two von Willebrand factor A (vWFA) domains (Table I) [de Kok et al., 1999]. Cochlin is the most highly expressed protein in the human and mouse inner ear, but its precise function remains unclear [Dessens et al., 2004; Robertson et al., 2006]. A possible role in either structural integrity or antimicrobial activity is predicted by its protein structure [Liepinsh et al., 2001] and immunohistochemistry of a temporal bone from a person with DFNA9-related deafness showing abundant aggregation of homogeneous acellular eosinophilic deposits with loss of cellularity in the cochlea and the vestibular labyrinth [Robertson et al., 2006].



Table I

DFNA9-causing mutations in the COCH gene



Most DFNA9-causing mutations are located within the LCCL domain, which is predicted to be involved in protein folding or a host-defense function (Table I) [Trexler et al., 2000]. The p.P51S variant that affects the LCCL module is the most frequently observed mutation in DFNA9 families [Bischoff et al., 2005; de Kok et al., 1999; Fransen et al., 2001; Fransen et al., 1999; Lemaire et al., 2003]. The identification of a large number of DFNA9 families carrying this variant has facilitated a detailed longitudinal analysis of the audiometric and vestibular impairment in 74 mutation carriers, which has shown that vestibular failure precedes and progresses more rapidly than hearing impairment [Bischoff et al., 2005].

In this study (approved by the University of Iowa Institutional Review Board), we recruited American subjects with ADNSHL and obtained DNA samples and audiograms. Audiograms were formatted for audioprofile analysis, which was conducted using the AudioGene v2.0 system [Hildebrand et al., 2008]. This system predicts the likely underlying genetic cause of hearing loss based on a number of different phenotypic parameters, including auditory thresholds, and rate of decrease in hearing relative to age and frequency. AudioGene v2.0 was trained with audiometric data from families with known deafness-causing mutations in KCNQ4 (DFNA2), DFNA5 (DFNA5), WFS1 (DFNA6/14/38), TECTA (DFNA8/12), COCH (DFNA9) and COL11A2 (DFNA13).

To validate AudioGene v2.0 as a clinical and research tool, we studied a cohort of 77 families segregating presumed ADSNHL represented by audiograms from 160 individuals. Individuals from seven families were identified by AudioGene v2.0 as having a DFNA9 profile, and in six families, mutation screening of the COCH gene was completed (genomic DNA was unavailable for screening in one family). While no mutations were identified in five families, one family was found to segregate the p.P51S mutation (positive predictive value, ∼16.7%) (Figs ​(Figs1,1, ​,2).2). To our knowledge, this family is the first outside Western Europe to be reported with this mutation. However by comparing highly heterozygous short tandem repeat polymorphisms (STRPs) tightly linked to the COCH gene, we could show that this family is related to five previously reported Belgian p.P51S families [Fransen et al., 2001] (data not shown), providing further evidence of a founder effect in the Benelux region of Western Europe.



Figure 1

Pedigree of the five-generation American family with nonsyndromic autosomal dominant HFSNHL, vestibular dysfunction and SSCD. Genotypes for nuceotide c.151 in the COCH gene are shown for those individuals included in the genetic analysis. Individuals ...





Figure 2

The causative mutation in the COCH gene in the American family. The mutation is a heterozygous C-to-T base change in exon 3 (c.151C→T) that results in substitution of a proline residue for a serine residue at position 51 (p.P51S).



The clinical presentation of all p.P51S families is very similar (Table I) [de Kok et al., 1999; Fransen et al., 2001; Fransen et al., 1999; Lemaire et al., 2003]. The hearing loss initially preferentially affects high frequencies (down-sloping) and progresses to become profound across all frequencies at a rate of ∼1.8 dB annually [Bom et al., 1999]. In a few exceptional cases, however, hearing at low frequencies declines much more rapidly, at greater than 24 dB annually [Bom et al., 1999]. In the American family, the self-reported age-of-onset of hearing loss ranged from 20 to 60 years. The hearing loss was progressive, with a general trend of initial moderate-to-severe high frequency (> 2000 Hz) hearing loss (HFSNHL) that became profound (Fig.3). In younger persons, the audioprofile was down-sloping, preserving hearing in the low and mid frequencies; with advancing age, low and mid frequency loss developed and the audioprofile flattened. Individuals IV:5 and IV:6 represent phenocopies.



Figure 3

Audiograms of representative affected family members at various ages. Affected individuals initially exhibit high frequency (> 2000 Hz) mild-to-moderate SNHL (HFSNHL) that progresses to become severe-to-profound before flattening out later in ...



All hearing impaired persons in this family excluding IV:5 and IV:6 also had vestibular impairment characterized by intermittent unsteadiness, particularly in the dark, and sporadic periods of dizziness. In addition, one person was diagnosed with Meniere’s-like symptoms and another with autoimmune inner ear disease requiring treatment with a diuretic and a low-salt diet. This variety of complaints is similar to that reported in other p.P51S families [Bischoff et al., 2005]. In general, p.P51S mutation carriers over 40 years of age usually have prominent vestibular symptoms however these complaints only emerge from the medical history if a targeted vestibular history is obtained.

Computed tomography (CT) scanning on a number of family members revealed intact ossicles, cochleae and semicircular canals with the exception of individual V:1. This person presented at age 31 in October, 2006, for an audiogram because of the family history of hearing loss. He has no complaints and by audiometry had 10 dB thresholds bilaterally through 2 kHz, a drop to 25 dB between 3-6 kHz, and normal hearing again at 8 kHz (Fig.4A). In February, 2008, he returned with a complaint of left aural fullness and persistent otalgia (6-9 months) and underwent temporal bone CT, which revealed bilateral superior semicircular canal dehiscence (SSCD) (Fig.4B).



Figure 4

Audiometry and temporal bone CT of individual V:1. A Audiogram recorded at 31 years of age showing slightly elevated hearing thresholds at high frequencies. B Coronial high-resolution CT scan of the temporal bones showing bilateral superior semicircular ...



SSCD is a rare disorder. Originally described by Minor and colleagues, it is characterized by the absence of bone overlying the superior semicircular canal, which creates a third labyrinthine window (with the oval and round windows) [Minor 2000; Minor 2005]. The consequence is the loss of acoustic energy and abnormal stimulation of the vestibular system; the clinical manifestations include Valsalva- and exercise-induced vertigo, sound-induced vertigo (Tullio phenomenon), and variable conductive hearing loss [Cox et al., 2003; Mikulec et al., 2004; Minor et al., 2003]. Diagnosis requires high resolution temporal bone CT [Belden et al., 2003; Hirvonen et al., 2003].

The genetics of SSCD have not been studied, and our finding of a COCH mutation in a single patient with SSCD is noteworthy since both DFNA9-related deafness and SSCD are rare. Although it seems unlikely that SSCD is directly related to the well-documented type of vestibular impairment that is part of the DFNA9 phenotype, SSCD may be present in other DFNA9 patients. We therefore recommend high resolution temporal bone CT in patients with DFNA9-related deafness and screening of COCH in sporadic or familial cases of SSCD. This diagnostic algorithm is important because SSCD and its associated symptoms can be partially or fully corrected with surgery [Carey et al., 2007; Limb et al., 2006; Mikulec et al., 2005; Wilkinson et al., 2008].

A remarkable finding in the process of identifying DFNA9/COCH as the underlying cause of deafness in this American family was not only that a dedicated computer program, AudioGene v2.0, hinted at this possibility, but that this occurred in the course of a screening procedure for DFNA2 families [Hildebrand et al., 2008]. It is reassuring to find that AudioGene v2.0 can distinguish between the audioprofiles of genetically different types of ADNSHL, especially when both DFNA2 and DFNA9 show remarkably similar high frequency hearing loss with steeply downsloping thresholds.

Admittedly, in the case of p.P51S mutation carriers genetic screening should be preferentially directed to DFNA9 and DFNA11, on the basis of the vestibular impairment findings. However, it is realistic to acknowledge the possibility that vestibular symptoms can go unnoticed. Furthermore, with other DFNA9/COCH mutations vestibular failure can be less prominent. It is not invariably penetrant and/or occurs at a more advanced age [Kemperman et al., 2005; Pauw et al., 2007a].

Mutation in the COCH gene is associated with superior semicircular canal dehiscence

Mutations in COCH (coagulation factor C homology) cause autosomal-dominant nonsyndromic hearing loss with variable degrees of clinical onset and vestibular malfunction. We selected eight uncharacterized mutations and performed immunocytochemical and Western blot analyses to track cochlin through the secretory pathway. We then performed a comprehensive analysis of clinical information from DFNA9 patients with all 21 known COCH mutations in conjunction with cellular and molecular findings to identify genotype-phenotype correlations. Our studies revealed that five mutants were not secreted into the media: two von Willebrand factor A (vWFA) domain mutants, which were not transported from the endoplasmic reticulum to Golgi complex and formed high-molecular-weight aggregates in cell lysates, and three LCCL domain mutants, which were detected as intracellular dimeric cochlins. Mutant cochlins that were not secreted and accumulated in cells result in earlier age of onset of hearing defects. In addition, individuals with LCCL domain mutations show accompanying vestibular dysfunction, whereas those with vWFA domain mutations exhibit predominantly hearing loss. This is the first report showing failure of mutant cochlin transport through the secretory pathway, abolishment of cochlin secretion, and formation and retention of dimers and large multimeric intracellular aggregates, and high correlation with earlier onset and progression of hearing loss in individuals with these DFNA9-causing mutations.

Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder.

Mutations in COCH (coagulation factor C homology) are etiologic for the late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. We introduced the G88E mutation by gene targeting into the mouse and have created a Coch(G88E/G88E) mouse model for the study of DFNA9 pathogenesis and cochlin function. Vestibular-evoked potential (VsEP) thresholds of Coch(G88E/G88E) mice were elevated at all ages tested compared with wild-type littermates. At the oldest ages, two out of eight Coch(G88E/G88E) mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds of Coch(G88E/G88E) mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, four of eight Coch(G88E/G88E) mice had absent ABRs at all frequencies tested and two of three Coch(G88E)(/+) mice had absent ABRs at three of four frequencies tested. Distortion product otoacoustic emission amplitudes of Coch(G88E/G88E) mice were substantially lower than Coch(+/+) mice and absent in the same Coch(G88E/G88E) mice with absent ABRs. These results suggest that vestibular function is affected beginning as early as 11 months when cochlear function appears to be normal, and dysfunction increases with age. Hearing loss declines substantially at 21 months of age and progresses to profound hearing loss at some to all frequencies tested. This is the only mouse model developed to date where hearing loss begins at such an advanced age, providing an opportunity to study both progressive age-related hearing loss and possible interventional therapies.

/pdf/a-targeted-coch-missense-mutation-a-knock-in-mouse-model-for-5ebozxulgn.pdf

A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction.

Seven missense mutations and one in-frame deletion mutation have been reported in the coagulation factor C homology (COCH) gene, causing the adult-onset, progressive sensorineural hearing loss and vestibular disorder at the DFNA9 locus. Prevalence of COCH mutations worldwide is unknown, as there is no systematic screening effort for late-onset hearing disorders; however, to date, COCH mutations have been found on four continents and the possibility of COCH playing an important role in presbycusis and disorders of imbalance has been considered. Cochlin (encoded by COCH) has also been shown as a major target antigen for autoimmune sensorineural hearing loss. In this report, we present histopathology, immunohistochemistry and proteomic analyses of inner ear tissues from post-mortem DFNA9 temporal bone samples of an individual from a large Dutch kindred segregating the P51S mutation and adult human unaffected controls, and wild-type (+/+) and Coch null (-/-) knock-out mice. DFNA9 is an inner ear disorder with a unique histopathology showing loss of cellularity and aggregation of abundant homogeneous acellular eosinophilic deposits in the cochlear and vestibular labyrinths, similar to protein aggregation in well-known neurodegenerative disorders. By immunohistochemistry on the DFNA9 temporal bone sections, we have shown cochlin staining of the characteristic cochlear and vestibular deposits, indicating aggregation of cochlin in the same structures in which it is normally expressed. Proteomic analysis identified cochlin as the most abundant protein in mouse and human cochleae. The high-level expression and stability of cochlin in the inner ear, even in the absence and severe atrophy of the fibrocytes that normally express COCH, are shown through these studies and further elucidate the pathobiologic events occurring in DFNA9 leading to hearing loss and vestibular dysfunction.

Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction.

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A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction.

Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction.