Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Abstract

Background tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 ( p < 2E −04 ), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes ( p < 2E −02 ). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus . ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.

Unification of Treatments and Interventions for Tinnitus Patients (UNITI): a study protocol for a multi-center randomized clinical trial

“…Paired-end whole-genome sequencing involves sequencing both ends of a DNA fragment, which increases the likelihood of alignment to the reference and facilitates detection of genomic rearrangements, repetitive sequences, and gene fusions. Gene burden tests will be used to compare burden of loss of function SNV and structural variants in synaptic genes in patients with tinnitus, using Non-Finnish European dataset from gnomAD v3 as population database to estimate allelic frequencies [ 62 ].…”

The Road Traveled and Journey Ahead for the Genetics and Genomics of Tinnitus

“…Exome sequencing of Spanish patients with Ménière’s disease and an extreme tinnitus phenotype uncovered 24 synaptic genes with an enrichment of rare missense variants [ 34 ]. A burden of rare variants in three candidate genes, ANK2 , TSC2 , and AKAP9 , was replicated in an independent Swedish cohort with severe tinnitus and was specific to the tinnitus phenotype through inclusion of data of patients with epilepsy who did not have tinnitus.…”

“…A burden of rare variants in three candidate genes, ANK2 , TSC2 , and AKAP9 , was replicated in an independent Swedish cohort with severe tinnitus and was specific to the tinnitus phenotype through inclusion of data of patients with epilepsy who did not have tinnitus. Gene-set enrichment analyses uncovered membrane trafficking and cytoskeletal binding in neurons [ 34 ]. This was the first study to link rare variants or large effect sizes to severe tinnitus and suggested genes associated with axonal branching and neuron connectivity in the brain.…”

Standardized Clinical Profiling in Spanish Patients with Chronic Tinnitus

“…The perceived impact of tinnitus can present a large interpersonal variability, and it can also vary over time. In addition, tinnitus can be considered as an annoying symptom in a small subgroup of patients [9]. There are no objective tests to determine the existence or severity of tinnitus, but there are many different standardized questionnaires to assess quality of life and annoyance related to tinnitus.…”