Genetics of Cerebellar and Vestibular Disorders

Abstract

Cerebellar and vestibular disorders are two groups of rare diseases with overlapping phenotypes with a strong genetic component. Previous studies had shown familial aggregation and few genes had been identified by segregation in large pedigrees. So, causal genes have remained unknown until the recent advances in next‐generation sequencing technologies, including whole‐exome sequencing (WES) as well as different bioinformatics approaches to elucidate and increase the lists of rare variants and novel genes associated with these disorders. WES have defined new genes as CLIC5 causing of DFNB102 and novel variants in TGM6, ELOVL4 or FXN genes associated with autosomal dominant and autosomal recessive hereditary ataxias. Vestibular disorders such as Meniere's disease or vestibular migraine also have a strong familial clustering with autosomal dominant inheritance, but no candidate genes have been identified in familial cases.

Key Concepts:

  • Cerebellar and vestibular disorders are two groups of rare diseases with a strong genetic component.

  • The clinical heterogeneity and the very low frequency of the causal variants can explain the slow progress in the knowledge of molecular genetics of vestibular and cerebellar disorders.

  • The bioinformatics analysis of rare variants and synonymous variants identified by NGS technology in multicase families is the best strategy to find out new genes associated with cerebellar and vestibular disorders.

  • Different bioinformatics approaches are needed to elucidate the genetic basis of cerebellar and vestibular disorders in order to find out causal variants leading to the development of new treatments.

  • A large number of causal mutations and genes will be described using NGS in vestibular and cerebellar disorders, but functional studies will be required to assess their impact on the phenotype.

Keywords: cerebellar disorder; vestibular disorder; ataxia; next‐generation sequencing; whole‐exome sequencing; genetics; candidate‐gene analysis

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Martin‐Sierra, Carmen, Requena, Teresa, and Lopez‐Escamez, Jose A(Oct 2014) Genetics of Cerebellar and Vestibular Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025827]