Variant Reclassification in Underrepresented Minority Children With Sensorineural Hearing Loss.

Objectives: Underrepresented minority (URM, comprising Hispanic, non-Hispanic Black, and Native American) children with sensorineural hearing loss have fivefold lower odds of receiving a genetic diagnosis after undergoing hearing loss gene-panel testing. Using hearing loss-specific American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines applied to a URM-specific cohort demonstrates the utility of these guidelines in reducing the disparity in diagnostic efficacy of genetic testing for URM populations.

Design: A total of 2740 variants from 715 patients with sensorineural hearing loss (1275 variants from 348 URM patients) were queried.

Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response (UPR), have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways have been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice.

Noise induces intercellular Ca signaling waves and the unfolded protein response in the hearing cochlea.

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response, have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways has been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice.

Synaptic ribbon dynamics after noise exposure in the hearing cochlea.

Moderate noise exposure induces cochlear synaptopathy, the loss of afferent ribbon synapses between cochlear hair cells and spiral ganglion neurons, which is associated with functional hearing decline. Prior studies have demonstrated noise-induced changes in the distribution and number of synaptic components, but the dynamic changes that occur after noise exposure have not been directly visualized. Here, we describe a live imaging model using RIBEYE-tagRFP to enable direct observation of pre-synaptic ribbons in mature hearing mouse cochleae after synaptopathic noise exposure.

TMTC4 is a hair cell-specific human deafness gene.

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene.