Unraveling the genotypic and phenotypic complexities of genetic hearing loss

Human molecular genetics and precision medicine are built upon an exquisite understanding of the nuanced relationship between DNA variants and human disease phenotypes. Unraveling this complexity is fundamental to realizing the promise of gene therapy and molecular interventions. However, in diseases that are extremely heterogeneous at the mutational, genetic and clinical levels, defining these relationships is extremely complicated. One such example of this complexity is genetic hearing loss.

Hearing loss is the most common sensory deficit. It is estimated to affect 538 million people worldwide, and by 2050, this number is predicted to grow to 1 billion. In developed countries, the majority of hearing loss has a genetic component. Over 150 genes are implicated in non-syndromic hearing loss (NSHL, hearing loss without other findings) while over 400 types of syndromic hearing loss (SHL) are known. With the advent of next-generation-sequencing, it has become commonplace to sequence all genes associated with NSHL simultaneously, and as a consequence, more than 6000 mutations have been linked to this condition.

To refine our understanding of the complex genetics of deafness, we have coupled human genomics, state-of-the-art technologies, in depth phenotyping, and functional studies to expose unrecognized mutation-gene-phenotype relationships in the CIB2, DFNA5, CEACAM16 and COL11A1 genes. Exposing these novel associations has direct impact on patient care and clinical practice. We have refuted the involvement of CIB2 in Usher Syndrome; revealed a novel phenotype associated with mutations in COL11A1; expanded the mutational mechanism associated with CEACAM16; and implicated coding variants in mRNA processing in DFNA5-related hearing loss. These novel discoveries have advanced our understanding of the biology of hearing, refined genetic diagnosis and identified novel targets for future molecular intervention.

Recognizing the need for a better understanding of the genomic landscape of deafness, we also created a deafness-specific variant database (the Deafness Variation Database; DVD). This unique resource collates the world community data on over 876,000 variants across 152 genes associated with genetic deafness. Because of this breadth, the DVD is now the primary resource for clinicians, genetic counselors and scientists in the auditory field, with more than 4000 users worldwide. By harnessing the extraordinary data provided by the DVD, we have gained insight into the mutational landscape of deafness. We have been able to show that each gene has its own mutational signature with minor allele frequency thresholds, variant effect, and protein domain as confounders to a variant’s effect. Understanding of these intricate mutationgene-phenotype nuances is foundational for improved accuracy in variant interpretation, refined clinical decision-making, and gene therapy for hearing loss.