Genetics of Cerebellar and Vestibular Disorders


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


Blakely EL, Alston CL, Lecky B et al. (2014) Distal weakness with respiratory insufficiency caused by the m.8344A>G “MERRF” mutation. Neuromuscular Disorders 24(6): 533–536.

Blanco‐Grau A, Bonaventura‐Ibars I, Coll‐Canti J et al. (2013) Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome. Genes, Brain, and Behaviour 12(8): 812–820.

Brusse E, Maat‐Kievit JA and van Swieten JC (2007) Diagnosis and management of early‐ and late‐onset cerebellar ataxia. Clinical Genetics 71(1): 12–24.

Cadieux‐Dion M, Turcotte‐Gauthier M, Noreau A et al. (2014) Expanding the clinical phenotype associated with ELOVL4 mutation: Study of a large French‐Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurology 71(4): 470–475.

Caramins M, Colebatch JG, Bainbridge MN et al. (2013) Exome sequencing identification of a GJB1 missense mutation in a kindred with X‐linked spinocerebellar ataxia (SCA‐X1). Human Molecular Genetics 22(21): 4329–4338.

Diogo D, Kurreeman F, Stahl EA et al. (2013) Rare, low‐frequency, and common variants in the protein‐coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis. American Journal of Human Genetics 92(1): 15–27.

Doi H, Yoshida K, Yasuda T et al. (2011) Exome sequencing reveals a homozygous SYT14 mutation in adult‐onset, autosomal‐recessive spinocerebellar ataxia with psychomotor retardation. American Journal of Human Genetics 89(2): 320–327.

Elsayed SM, Heller R, Thoenes M et al. (2014) Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations. European Journal of Human Genetics 22(2): 286–288.

Evans‐Galea MV, Lockhart PJ, Galea CA, Hannan AJ and Delatycki MB (2014) Beyond loss of frataxin: the complex molecular pathology of Friedreich ataxia. Discovery Medicine 17(91): 25–35.

Feinstein M, Flusser H, Lerman‐Sagie T et al. (2014) VPS53 mutations cause progressive cerebello‐cerebral atrophy type 2 (PCCA2). Journal of Medical Genetics 51(5): 303–308.

Gazquez I and Lopez‐Escamez JA (2011) Genetics of recurrent vertigo and vestibular disorders. Current Genomics 12(6): 443–450.

Gazquez I, Moreno A, Aran I et al. (2012) MICA‐STR A.4 is associated with slower hearing loss progression in patients with Ménière's disease. Ontology & Neurotology 33(2): 223–229.

Gilissen C, Hoischen A, Brunner HG and Veltman JA (2011) Unlocking Mendelian disease using exome sequencing. Genome Biology 12(9): 228.

Gopen Q, Zhou G, Whittemore K and Kenna M (2011) Enlarged vestibular aqueduct: review of controversial aspects. The Laryngoscope 121(9): 1971–1978.

Hehir‐Kwa JY, Wieskamp N, Webber C et al. (2010) Accurate distinction of pathogenic from benign CNVs in mental retardation. PLoS Computational Biology 6(4): e1000752.

Hersheson J, Haworth A and Houlden H (2012) The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Human mutation 33(9): 1324–1332.

Hildebrand MS, Tack D, Deluca A et al. (2009) Mutation in the COCH gene is associated with superior semicircular canal dehiscence. American Journal of Medical Genetics Part A 149A (2): 280–285.

Jayadev S and Bird TD (2013) Hereditary ataxias: overview. Genetics in Medicine: Official Journal of the American College of Medical Genetics 15(9): 673–683.

Jonard L, Niasme‐Grare M, Bonnet C et al. (2010) Screening of SLC26A4, FOXI1 and KCNJ10 genes in unilateral hearing impairment with ipsilateral enlarged vestibular aqueduct. International Journal of Pediatric Otorhinolaryngology 74(9): 1049–1053.

Kim HJ, Won HH, Park KJ et al. (2013) SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late‐onset nonsyndromic hearing loss (DFNA15). PLoS One 8(11): e79063.

Lee YC, Durr A, Majczenko K et al. (2012) Mutations in KCND3 cause spinocerebellar ataxia type 22. Annals of Neurology 72(6): 859–869.

Li H, Teo YY and Tan EK (2013) Patterns of linkage disequilibrium of LRRK2 across different races: implications for genetic association studies. PLoS One 8(9): e75041.

Madden C, Halsted M, Meinzen‐Derr J et al. (2007) The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct. Archives of Otolaryngology – Head & Neck Surgery 133(2): 162–168.

Rabbani B, Tekin M and Mahdieh N (2014) The promise of whole‐exome sequencing in medical genetics. Journal of Human Genetics 59(1): 5–15.

Requena T, Espinosa‐Sanchez JM and Lopez‐Escamez JA (2014) Genetics of dizziness: cerebellar and vestibular disorders. Current Opinion in Neurology 27(1): 98–104.

Requena T, Gazquez I, Moreno A et al. (2013). Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere's disease. Immunogenetics 65(5) :345–355.

Reyes S, Wang G, Ouyang X et al. (2009) Mutation analysis of SLC26A4 in mainland Chinese patients with enlarged vestibular aqueduct. Otolaryngology – Head and Neck Surgery 141(4): 502–508.

Robinson PN, Kohler S, Oellrich A et al. (2014) Improved exome prioritization of disease genes through cross‐species phenotype comparison. Genome Research 24(2): 340–348.

Rossi M, Perez‐Lloret S, Doldan L et al. (2014) Autosomal dominant cerebellar ataxias: a systematic review of clinical features. European Journal of Neurology 21(4): 607–615.

Ruano L, Melo C, Silva MC and Coutinho P (2014) The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42(3): 174–183.

Salehi MH, Kamalidehghan B, Houshmand M et al. (2014) Gene expression profiling of mitochondrial oxidative phosphorylation (OXPHOS) complex I in Friedreich ataxia (FRDA) patients. PLoS One 9(4): e94069.

Sang Q, Yan X, Wang H et al. (2013) Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11). PLoS One 8(1): e55178.

Sauna ZE and Kimchi‐Sarfaty C (2011) Understanding the contribution of synonymous mutations to human disease. Nature Reviews Genetics 12(10): 683–691.

Seco CZ, Oonk AM, Domínguez‐Ruiz M et al. (2014) Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. European Journal of Human Genetics: EJHG. doi:10.1038/ejhg.2014.83. [Epub ahead of print].

Shakkottai VG and Fogel BL (2013) Clinical neurogenetics: autosomal dominant spinocerebellar ataxia. Neurologic Clinics 31(4): 987–1007.

Staab JP (2011) Clinical clues to a dizzying headache. Journal of Vestibular Research: Equilibrium & Orientation 21(6): 331–340.

Szmulewicz DJ, McLean CA, Rodriguez ML et al. (2014) Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS. Neurology 82(16): 1410–1415.

Szmulewicz DJ, Waterston JA, MacDougall HG et al. (2011) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video‐oculographic diagnosis. Annals of the New York Academy of Sciences 1233: 139–147.

Vermeer S, van de Warrenburg BP, Willemsen MA et al. (2011) Autosomal recessive cerebellar ataxias: the current state of affairs. Journal of Medical Genetics 48(10): 651–659.

Wang JL, Yang X, Xia K et al. (2010) TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain: A Journal of Neurology 133(Pt 12): 3510–3518.

Winkelmann J, Lin L, Schormair B et al. (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Human Molecular Genetics 21(10): 2205–2210.

Zeviani M, Simonati A and Bindoff LA (2012) Ataxia in mitochondrial disorders. Handbook of Clinical Neurology 103: 359–372.

Zhang X (2014) Exome sequencing greatly expedites the progressive research of Mendelian diseases. Frontiers of Medicine 8(1): 42–57.

Zhao M, Wang Q, Wang Q, Jia P and Zhao Z (2013) Computational tools for copy number variation (CNV) detection using next‐generation sequencing data: features and perspectives. BMC Bioinformatics 14(Suppl. 11): S1.

Further Reading

Cheung VG and Spielman RS (2009) Genetics of human gene expression: mapping DNA variants that influence gene expression. Nature Reviews Genetics 10(9): 595–604.

Jen JC, Graves TD, Hess EJ et al. (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130(10): 2484–2493.

Johansen Taber KA, Dickinson BD and Wilson M (2014) The promise and challenges of next‐generation genome sequencing for clinical care. JAMA Internal Medicine 174(2): 275–280.

Lempert T, Olesen J, Furman J et al. (2012) Vestibular migraine: diagnostic criteria. Journal of Vestibular Research 22(4) :167–172.

Smeets CJ and Verbeek DS (2014) Cerebellar ataxia and functional genomics: identifying the routes to cerebellar neurodegeneration. Biochimica et Biophysica Acta. doi:10.1016/j.bbadis.2014.04.004.

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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. [doi: 10.1002/9780470015902.a0025827]