Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

OBJECTIVES: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. DESIGN: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. RESULTS: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. CONCLUSIONS: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

[Hereditary hearing loss]. / Hereditäre Schwerhörigkeit.

Understanding the genetic basis of hearing loss is becoming increasingly relevant, as 50-70% of congenital hearing loss is hereditary and postlingual hearing loss is also often of hereditary origin. To date, more than 220 genes for hearing loss have been identified and more than 600 syndromes with hearing loss described. This review article explains the classification of genetic hearing loss into syndromic versus non-syndromic forms and the modes of inheritance involved. Some of the most common syndromes (Usher, Pendred, Jervell-Lange-Nielsen, Waardenburg, branchiootorenal, and Alport syndrome) are introductorily described. New sequencing technologies have significantly expanded the diagnostic options for genetic hearing loss and made them more accessible. This text aims to encourage initiation of genetic diagnosis in hearing-impaired patients with suspected hereditary genesis in order to provide the best possible counseling for affected individuals and their families.

Accessing the stapedius muscle via novel surgical retrofacial approach during cochlear implantation surgery: Intraoperative results on feasibility and safety.

Human stapedius muscle (SM) can be directly and safely accessed via retrofacial approach, opening new approaches to directly measure the electrically evoked stapedius reflex threshold (eSRT). The measurement of the SM activity via direct surgical access represents a potential tool for objective eSRT fitting of cochlear implants (CI), increasing the benefit experienced by the CI users and leading to new perspectives in the development of smart implantable neurostimulators. 3D middle-ear reconstructions created after manual segmentation and related SM accessibility metrics were evaluated before the CI surgery for 16 candidates with assessed stapedius reflex. Retrofacial approach to access the SM was performed after facial recess exposure. In cases of poor exposition of SM, the access was performed anteriorly to the FN via drilling of the pyramidal eminence (PE). The total access rate of the SM via both the retrofacial and anterior approach of the FN was 100%. In 81.2% of cases (13/16), the retrofacial approach allowed to access the SM on previously categorized well exposed (8/8), partially exposed (4/5), and wholly concealed (1/3) SM with respect to FN. Following intraoperative evaluation in the remaining 18.8% (3/16), the SM was accessed anteriorly via drilling of the PE. Exposure of SM with respect to the FN and the sigmoid sinus's prominence was a predictor for the suitable surgical approach. The retrofacial approach offers feasible and reproducible access to the SM belly, opening direct access to electromyographic sensing of the eSRT. Surgical planner tools can quantitatively assist pre-surgical assessment.

Diagnostic Yield of Targeted Hearing Loss Gene Panel Sequencing in a Large German Cohort With a Balanced Age Distribution from a Single Diagnostic Center: An Eight-year Study.

OBJECTIVES: Hereditary hearing loss exhibits high degrees of genetic and clinical heterogeneity. To elucidate the population-specific and age-related genetic and clinical spectra of hereditary hearing loss, we investigated the sequencing data of causally associated hearing loss genes in a large cohort of hearing-impaired probands with a balanced age distribution from a single center in Southwest Germany. DESIGN: Genetic testing was applied to 305 hearing-impaired probands/families with a suspected genetic hearing loss etiology and a balanced age distribution over a period of 8 years (2011-2018). These individuals were representative of the regional population according to age and sex distributions. The genetic testing workflow consisted of single-gene screening (n = 21) and custom-designed hearing loss gene panel sequencing (n = 284) targeting known nonsyndromic and syndromic hearing loss genes in a diagnostic setup. Retrospective reanalysis of sequencing data was conducted by applying the current American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. RESULTS: A genetic diagnosis was established for 75 (25%) of the probands that involved 75 causal variants in 35 genes, including 16 novel causal variants and 9 medically significant variant reclassifications. Nearly half of the solved cases (47%; n = 35) were related to variants in the five most frequently affected genes: GJB2 (25%), MYO15A, WFS1, SLC26A4, and COL11A1 (all 5%). Nearly one-quarter of the cases (23%; n = 17) were associated with variants in seven additional genes (TMPRSS3, COL4A3, LOXHD1, EDNRB, MYO6, TECTA, and USH2A). The remaining one-third of single cases (33%; n = 25) were linked to variants in 25 distinct genes. Diagnostic rates and gene distribution were highly dependent on phenotypic characteristics. A positive family history of autosomal-recessive inheritance in combination with early onset and higher grades of hearing loss significantly increased the solve rate up to 60%, while late onset and lower grades of hearing loss yielded significantly fewer diagnoses. Regarding genetic diagnoses, autosomal-dominant genes accounted for 37%, autosomal-recessive genes for 60%, and X-linked genes for 3% of the solved cases. Syndromic/nonsyndromic hearing loss mimic genes were affected in 27% of the genetic diagnoses. CONCLUSIONS: The genetic epidemiology of the largest German cohort subjected to comprehensive targeted sequencing for hereditary hearing loss to date revealed broad causal gene and variant spectra in this population. Targeted hearing loss gene panel analysis proved to be an effective tool for ensuring an appropriate diagnostic yield in a routine clinical setting including the identification of novel variants and medically significant reclassifications. Solve rates were highly sensitive to phenotypic characteristics. The unique population-adapted and balanced age distribution of the cohort favoring late hearing loss onset uncovered a markedly large contribution of autosomal-dominant genes to the diagnoses which may be a representative for other age balanced cohorts in other populations.

Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.

Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of autosomal dominant nonsyndromic hearing loss due to a splice-altering variant in COL11A1, mapping the DFNA37 locus. Here, we describe two German families presenting prelingual autosomal dominant nonsyndromic hearing loss with novel COL11A1 heterozygous splice-altering variants (c.652-1G>C and c.4338+2T>C) that were molecularly characterized. Interestingly, the c.652-1G>C variant affects the same intron 4 canonical splice site originally reported in the DFNA37 family (c.652-2A>C) but elicits a different splicing outcome. Furthermore, the c.4338+2T>C variant originated de novo. We provide clinical and molecular genetic evidence to unambiguously confirm that COL11A1 splice-altering variants cause DFNA37 hearing loss and affirm that COL11A1 be included in the genetic testing of patients with nonsyndromic deafness.

Calcium signaling in interdental cells during the critical developmental period of the mouse cochlea.

The tectorial membrane (TM), a complex acellular structure that covers part of the organ of Corti and excites outer hair cells, is required for normal hearing. It consists of collagen fibrils and various glycoproteins, which are synthesized in embryonic and postnatal development by different cochlear cell types including the interdental cells (IDCs). At its modiolar side, the TM is fixed to the apical surfaces of IDCs, which form the covering epithelium of the spiral limbus. We performed confocal membrane imaging and Ca2+ imaging in IDCs of the developing mouse cochlea from birth to postnatal day 18 (P18). Using the fluorescent membrane markers FM 4-64 and CellMask™ Deep Red on explanted whole-mount cochlear epithelium, we identified the morphology of IDCs at different z-levels of the spiral limbus. Ca2+ imaging of Fluo-8 AM-loaded cochlear epithelia revealed spontaneous intracellular Ca2+ transients in IDCs at P0/1, P4/5, and P18. Their relative frequency was lowest on P0/1, increased by a factor of 12.5 on P4/5 and decreased to twice the initial value on P18. At all three ages, stimulation of IDCs with the trinucleotides ATP and UTP at 1 and 10 µM elicited Ca2+ transients of varying amplitude and shape. Before the onset of hearing, IDCs responded with robust Ca2+ oscillations. At P18, after the onset of hearing, ATP stimulation either caused Ca2+ oscillations or an initial Ca2+ peak followed by a plateau while the UTP response was unchanged from that at pre-hearing stage. Parameters of spontaneous and nucleotide-evoked Ca2+ transients such as amplitude, decay time and duration were markedly reduced during cochlear development, whereas the kinetics of the Ca2+ rise did not show relevant changes. Whether low-frequency spontaneous Ca2+ transients are necessary for the formation and maintenance of the tectorial membrane e.g. by regulating gene transcription needs to be elucidated in further studies.