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The Jian et al. study uncovered many carriers for hearing loss and even two newborns with biallelic likely pathogenic/pathogenic variants in GJB2 (OMIM: 121011) and four with pathogenic MT-RNR1 (OMIM: 561000) variants, all in children who reportedly passed universal newborn hearing screening evaluation. Emerging gene therapies for hearing impairment require a morphologically intact auditory system, as suggested by normal newborn hearing screening results, revealing a potential critical therapeutic window for two newborns with one of the most common forms of pediatric onset deafness (GJB2) or preventative knowledge about aversion to ototoxic drugs (MT-RNR1) in an additional four newborns. Considerations with respect to information that has an immediate diagnostic value at the time of birth versus the possibility to support research and therapeutic development following the newborn period should be distinctly separated. If a genetic cause of an adult onset disorder is identified in the genome of a child, it is possible that other family members either currently have or are at risk for the disorder, making the family the possible immediate beneficiary instead of the child, complicating the individual's right ‘(not) to know’.

The OTOF gene encodes otoferlin, a critical protein at the synapse of auditory sensory cells, the inner hair cells (IHCs). In the absence of otoferlin, signal transmission of IHCs fails due to impaired release of synaptic vesicles at the IHC synapse. Biallelic pathogenic and likely pathogenic variants in OTOF predominantly cause autosomal recessive profound prelingual deafness, DFNB9. Due to the isolated defect of synaptic transmission and initially preserved otoacoustic emissions (OAEs), the clinical characteristics have been termed “auditory synaptopathy”. We review the broad phenotypic spectrum reported in patients with variants in OTOF that includes milder hearing loss, as well as progressive and temperature-sensitive hearing loss. We highlight several challenges that must be addressed for rapid clinical and genetic diagnosis. Importantly, we call for changes in newborn hearing screening protocols, since OAE tests fail to diagnose deafness in this case. Continued research appears to be needed to complete otoferlin isoform expression characterization to enhance genetic diagnostics. This timely review is meant to sensitize the field to clinical characteristics of DFNB9 and current limitations in preparation for clinical trials for OTOF gene therapies that are projected to start in 2021.

The approval of investigational drugs for five adeno-associated virus-based gene replacement therapies marked a historic milestone in the journey to treat the first hereditary form of hearing impairment, auditory synaptopathy, caused by deleterious variants in the otoferlin gene (OTOF, DFNB9)1. Three of these approvals were granted by the U.S. Food and Drug Administration and European Medicines Agency in 2022/2023 and represented pivotal advancements, paving the way for clinical trials by one French-based and two American-based companies. In late 2023, the earliest results from the first-in-human otoferlin trial were presented at the European Society of Gene and Cell Therapy meeting in Brussels, Belgium (https://www.esgct.eu/) by Dr. Shu Yilai and colleagues from China, making headlines in the press (https://www.technologyreview.com/2023/11/01/1082740/china-gene-therapty-deafness-hearing/). This pioneering work, published in January 20242,3, added substantial knowledge to the unfolding narrative, which also includes a recent press release from Akouos describing a successful one-month follow-up in a single treated patient (https://www.genengnews.com/topics/translational-medicine/gene-therapy-restores-hearing-in-11-year-old-after-just-one-month/). While early trial reports are cautiously optimistic, offering promising outcomes on safety and efficacy to date, open questions remain, including the durable safety and efficacy of these therapies in humans, as well as the implementation of harmonized and appropriate outcome measures. As we anticipate the development of efficient hearing-restoring OTOF gene therapies, we describe the inception of the first patient registry for patients with otoferlin-related auditory synaptopathy and the first gene-specific registry for an isolated form of hearing loss (NCT05946057), drawing inspiration from the existing registries for syndromic forms of hearing loss. This way, we mark yet another step forward in the evolving landscape of clinical trials on otoferlin-related auditory synaptopathy. KCI Citation Count: 0

Graphical abstract The many syndromes involving hearing loss.

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade. Graphical Abstract This review summarizes the clinical translation of gene therapy and cochlear implant innovations and discusses if there is an unmet medical need for improving hearing restoration.

Tinnitus is the perception of a phantom sound that affects between 10 and 15% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.

Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m 6 A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3 -knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m 6 A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m 6 A-modified PSEN1 , while decreased METTL3-mediated m 6 A methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.

The transport and Golgi organization 1 (TANGO1) proteins play pivotal roles in the secretory pathway. Full length TANGO1 is a transmembrane protein localised at endoplasmic reticulum (ER) exit sites, where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment to create an exit route for their export. Here we report the first TANGO1-associated syndrome in humans. A synonymous substitution that results in exon eight skipping in most mRNA molecules, ultimately leading to a truncated TANGO1 protein was identified as disease-causing mutation. The four homozygously affected sons of a consanguineous family display severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the corresponding truncated TANGO1 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1 impairs cellular collagen I secretion.

Background Tooth agenesis is a common dental anomaly that can substantially affect both the ability to chew and the esthetic appearance of patients. This study aims to identify possible genetic factors that underlie various forms of tooth agenesis and to investigate the possible molecular mechanisms through which human dental pulp stem cells may play a role in this condition. Results Using whole-exome sequencing of a Han Chinese family with non-syndromic tooth agenesis, a rare mutation in FGFR1 (NM_001174063.2: c.103G > A, p.Gly35Arg) was identified as causative and confirmed by Sanger sequencing. Via GeneMatcher, another family with a known variant (NM_001174063.2: c.1859G > A, p.Arg620Gln) was identified and diagnosed with tooth agenesis and a rare genetic disorder with considerable intrafamilial variability. Fgfr1 is enriched in the ectoderm during early embryonic development of mice and showed sustained low expression during normal embryonic development of Xenopus laevis frogs. Functional studies of the highly conserved missense variant c.103G > A showed deleterious effects. FGFR1 (c.103G > A) was overexpressed compared to wildtype and promoted proliferation while inhibiting apoptosis in HEK293 and human dental pulp stem cells. Moreover, the c.103G > A variant was found to suppress the epithelial-mesenchymal transition. The variant could downregulate ID4 expression and deactivate the TGF-beta signaling pathway by promoting the expression of SMAD6 and SMAD7. Conclusion Our research broadens the mutation spectrum associated with tooth agenesis and enhances understanding of the underlying disease mechanisms of this condition.