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In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3'-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Otosclerosis is a common form of hearing loss (HL) due to abnormal remodeling of the otic capsule. The genetic causes of otosclerosis remain largely unidentified. Only mutations in a single gene, SERPINF1, were previously published in patients with familial otosclerosis. To unravel the contribution of genetic variation in this gene to otosclerosis, this gene was re-sequenced in a large population of otosclerosis patients and controls. Resequencing of the 5' and 3' UTRs, coding regions, and exon-intron boundaries of SERPINF1 was performed in 1604 unrelated otosclerosis patients and 1538 unscreened controls, and in 62 large otosclerosis families. Our study showed no enrichment of rare variants, stratified by type, in SERPINF1 in patients versus controls. Furthermore, the c.392C > A (p.Ala131Asp) variant, previously reported as pathogenic, was identified in three patients and four controls, not replicating its pathogenic nature. We could also not find evidence for a pathogenic role in otosclerosis for 5' UTR variants in the SERPINF1-012 transcript (ENST00000573763), described as the major transcript in human stapes. Furthermore, no rare variants were identified in the otosclerosis families. This study does not support a pathogenic role for variants in SERPINF1 as a cause of otosclerosis. Therefore, the etiology of the disease remains largely unknown and will undoubtedly be the focus of future studies.

Purpose: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis., Methods: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls., Results: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060)., Conclusion: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Objectives: The aim of this study was to define the typical pattern for varicella zoster virus (VZV) reactivation in delayed facial palsy (DFP) after stapedectomy for otosclerosis., Materials and Methods: Review of the relevant literature, personal casistics, and case-report., Results: In total, 48 cases of DFP after stapes surgery have been described so far, including the reported case with exclusive manifestation of atypical Ramsay Hunt syndrome (RH); in the personal series of 1253 stapedectomies, DFP occurred in only one case (0.08%). Complete DFP (House-Brackmann grade VI) rapidly developed 12 days after surgery; RH appeared 2 days later, confirming the role of VZV. The DFP started improving after 8 weeks and completely recovered 6 months later., Conclusion: Acute otalgia prior to DFP should raise the suspicion of VZV reactivation. Atypical RH is the most frequent pattern that occurs in DFP after stapedectomy.