Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.

Motivation: Transcription factors binding events depend not only on a specific DNA motif but also on the chromatin context. To further explore this new transcriptional machinery level of complexity, we developed TFregulomeR, a MethMotif API R-library that facilitates batch queries. Our toolbox showed how the functions of TFs depend on cofactors, whose recruitment are also influenced by DNA methylation. This observation led us to release a new version of MethMotif that includes, in addition to more methyl-TF motifs and more organisms (Mus Musculus and Arabidopsis Thaliana), new features to discern context-specific TFs’ motifs associated with context-specific TFs' functions. Results: Using TFregulomeR, we expanded the range of information available in the new release of MethMotif by segregating TF’s binding motifs in the context of their cofactors and DNA methylation status. This strategy enabled us to build the first TF binding motifs database that incorporates context-specific position weight matrices coupled to epigenetic information and context-specific TFs’ function. Using this repository, we were able to further demonstrate that gene ontology (GO) enriched terms associated with transcription factor target genes may differ notably based on association with alternative cofactors and DNA methylation status. Conclusions: Overall, this update turns MethMotif into an integrative TF motif database with diverse regulatory element analysis tools accessible to a broad audience. Ultimately, this repository and its companion tools greatly facilitate the analysis of the consequences of epigenetic aberrations seen in diseases such as cancers. Availability: The MethMotif database is freely available at https://methmotif.org.