Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study
Metadatos
Mostrar el registro completo del ítemAutor
Amanat, Sana; Gallego Martinez, Álvaro; Pérez Carpena, Patricia; Espinosa Sánchez, Juan Manuel; López Escámez, José AntonioEditorial
ELSEVIER
Materia
Tinnitus Extreme phenotype Axon initial segment Exome sequencing
Fecha
2021Referencia bibliográfica
Amanat, S., Gallego-Martinez, A., Sollini, J., Perez-Carpena, P., Espinosa-Sanchez, J. M., Aran, I., ... & Lopez-Escamez, J. A. (2021). Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study. EBioMedicine, 66, 103309.
Resumen
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.