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Journal of Neurology (2018) 265 (Suppl 1):S29–S34
https://doi.org/10.1007/s00415-018-8842-7
REVIEW
Genetic contribution tovestibular diseases
AlvaroGallego‑Martinez1· JuanManuelEspinosa‑Sanchez1,3· JoseAntonioLopez‑Escamez1,2,3
Received: 28 January 2018 / Revised: 18 March 2018 / Accepted: 20 March 2018 / Published online: 26 March 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Growing evidence supports the contribution of allelic variation to vestibular disorders. Heritability attributed to rare allelic
variants is found in familial vestibular syndromes such as enlarged vestibular aqueduct syndrome or familial Meniere dis‑
ease. However, the involvement of common allelic variants as key regulators of physiological processes in common and
rare vestibular diseases is starting to be deciphered, including motion sickness or sporadic Meniere disease. The genetic
contribution to most of the vestibular disorders is still largely unknown. This review will outline the role of common and rare
variants in human genome to episodic vestibular syndromes, progressive vestibular syndrome, and hereditary sensorineural
hearing loss associated with vestibular phenotype. Future genomic studies and network analyses of omic data will clarify
the pathway towards a personalized stratification of treatments.
Keywords Dizziness· Vestibular disorders· Genetics· Meniere disease· Vestibular migraine
Phenotype heterogeneity investibular
diseases
Vestibular disorders include a group of inner ear diseases
involving the posterior labyrinth, but also the connections
between the labyrinth and the brainstem. Vertigo, dizziness,
and unsteadiness are the main symptoms of vestibular dis‑
orders, although other symptoms like oscillopsia could also
be present in these patients. The clinical phenotype can vary
not only according to the type of symptoms, but also to the
age of onset, the progression of disease symptoms, and the
association with other comorbidities. The lack of biomarkers
implies that the diagnosis of these disorders relies on clinical
criteria; however, some patients present overlapping symp‑
toms and the clinical diagnosis is not clear [1, 2].
The Bárány Society has promoted an International Clas‑
sification of Vestibular Disorders that includes three main
syndromes: acute vestibular syndrome, episodic vestibular
syndrome, and chronic vestibular syndrome [3].
The role of inheritance in vestibular disorders has grow‑
ing evidence [4, 5] and it is supported by epidemiological
studies, including the familiar aggregation described for
some diseases and a higher prevalence in some ethnical
groups [6]. Familial vestibular disorders segregate accord‑
ing to aMendelian inheritance pattern, but incomplete pen‑
etrance is observed [7]. Therefore, some individuals present
the vestibular phenotype, while others do not exhibit it, even
though they carry identical mutant alleles.
Vestibular disorders are also characterized by variable
expressivity. This means that individuals with the same
genotype can also show different degrees of the same phe‑
notype. Recent discoveries on vestibular disorder genetics
show difficulties linking common or rare variants with the
severity of symptoms, since regulatory variants and epige‑
netic modifications can contribute significantly to phenotype
variation [7].
This manuscript is part of a supplement sponsored by the German
Federal Ministry of Education and Research within the funding
initiative for integrated research and treatment centers.
* Jose Antonio Lopez‑Escamez
antonio.lopezescamez@genyo.es
1 Otology andNeurotology Group CTS495, Department
ofGenomic Medicine, Centre forGenomics andOncological
Research‑Pfizer/University ofGranada/Andalusian Regional
Government (GENYO), Avda de la Ilustración, 114,
18016Granada, Spain
2 Luxembourg Centre forSystems Biomedicine (LCSB),
University ofLuxembourg, Esch‑sur‑Alzette, Luxembourg
3 Department ofOtolaryngology, Instituto de Investigación
Biosanitaria ibs.GRANADA, Hospital Universitario Virgen
de las Nieves, Granada, Spain
S30 Journal of Neurology (2018) 265 (Suppl 1):S29–S34
1 3
Episodic vestibular syndromes
The clinical presentation of vestibular disorders usually
occurs in the form of episodes of vertigo or dizziness and
they are characterized by complete or partial restoration of
the vestibular function after each attack. Motion sickness
(MoS) and vestibular migraine (VM) are the most common
vestibular disorders, and both of them seem to have a poten‑
tial genetic component [5, 6].
Epidemiological and clinical data suggest that the epi‑
sodic vestibular syndrome could be associated with hear‑
ing loss and/or migraine and it should be considered as a
clinical spectrum ranging from bilateral Meniere’s disease
(MD; extreme phenotype with hearing loss associated with
rare variants in families) to migraine without aura (mild
phenotype associated with hundreds of rare and common
variants). Therefore, several intermediate phenotypes could
be considered such us unilateral MD, VM, or migraine with
aura; and they would form a continuum of symptoms able
to explain the variable expressivity (Fig.1).
Motion sickness
Motion sickness is a very common disorder characterized
by dizziness, nausea, and vomiting, and other autonomic
symptoms that appear in specific situations where there is a
sensory mismatch between the subjective expected vertical
and the sensed vertical. When using mean of transport, but
also in virtual reality condition and simulators, a conflict
between visuo‑vestibular, canal–otolith, and utricle–saccule
inputs may arise. MoS is not a primarily vestibular disorder;
it is the result of a combined transient mismatch of vestibular
and visual information with vagal dysfunction. However, the
causes of this condition are not well understood, and a high
heritability is observed.
A large genome‑wide association study (GWAS) con‑
ducted in 80,494 individuals with MoS found 35 single‑
nucleotide variants (SNVs) associated [8]. A few associated
SNVs are located in genes involved in eye and ear develop‑
ment or in the synthesis of otoliths. Several other associ‑
ated SNVs are located near genes involved in neurologi‑
cal processes including synapse development and function.
However, other associated SNVs are in regions involved in
glucose and insulin homeostasis, and hypoxia, suggesting a
role of glucose levels and a potential relationship between
MoS and hypoxia.
Vestibular migraine
Vestibular migraine is a common disorder that occurs in
patients with the previous or current history of migraine who
experience recurrent episodes of vestibular symptoms with
migrainous features during these attacks. Although VM is
underdiagnosed, it is considered the second most common
cause of episodic vertigo after benign paroxysmal positional
vertigo. The pathophysiology of VM is poorly understood
and several hypotheses have been proposed [9]. There is no
biological marker for VM, so the diagnosis is made on the
basis of the clinical history according to clinical diagnostic
criteria [10].
Familial occurrence of VM supports the hypothesis of
heritability with an autosomal dominant inheritance pattern
and incomplete penetrance [11]. Nevertheless, although
GWAS have revealed linkage to chromosome 5q35, 11q, and
22q12, no candidate gene has been validated. Mutations in
the CACNA1A gene, which encodes the central pore‑form‑
ing subunit of the voltage‑gated CaV2.1 (P/Q‑type) calcium
channels, cause three neurological calcium channelopathies:
episodic ataxia type 2, familial hemiplegic migraine type 1,
and spinocerebellar ataxia type 6 [6]; however, its relation‑
ship to VM has not been demonstrated.
Progressive vestibular syndromes
This category includes diseases with a progressive loss of
vestibular function, which might be affected by the genetic
background.
Fig. 1 Episodic vestibular syndrome (EVS) model. Disorders are
ranked according to their prevalence. The number of allelic variants
(or genes) involved in each disorder is associated with its preva‑
lence. Therefore, rare diseases such as familial Meniere disease are
associated with few genes and motion sickness will be associated
with hundred of genes. This model aims to explain clinical hetero‑
geneity found in the EVS based on the combined additive effect of
genetic and epigenetic variation with different environmental triggers.
Vestibular migraine and MD are defined by a set of core symptoms
(complete phenotype). Some individuals may have only some of these
symptoms (incomplete phenotype), although others may share diag‑
nostic criteria for both disorders (overlap phenotype)
S31Journal of Neurology (2018) 265 (Suppl 1):S29–S34
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Vestibular schwannoma
Vestibular schwannomas (VS) are slow‑growing benign
Schwann cell tumors that initiate along the vestibulococh‑
lear nerve, usually from the vestibular part. Common symp‑
toms of VS are hearing loss, tinnitus, dizziness, and facial
paresthesia. Depending on whether it affects one or both
vestibulocochlear nerves, VS are classified into unilateral
or bilateral VS, respectively. The most common form of VS
affects only one vestibulocochlear nerve, representing about
95% of cases. Few rare cases develop bilateral VS, com‑
monly linked to neurofibromatosis type 2 (NF2), a known
autosomal dominant disease caused by mutations in the NF2
gene [12].
Moreover, the microRNA miR‑1 seems to affect to the
development of the tumor growth by regulating cell prolif‑
eration and apoptosis on tumor cells, and it could be consid‑
ered as a new therapeutic target for VS [13]. A whole‑exome
sequencing (WES) study on 46 sporadic unilateral VS cases
shows that VS exhibit large heterogeneity; however, variants
in NF2 gene were detected in a large number of cases. Most
of the rare variants were found in axonal guidance path‑
way genes, and CDC27 and USP8 genes were considered as
novel oncogenic candidates [14].
Enlarged vestibular aqueduct syndrome
The enlargement of the vestibular aqueduct syndrome
(EVAS) is a developmental disorder of the inner ear where
the vestibular aqueduct expands and dilates. EVAS is usu‑
ally associated with two different disorders, according to
the presence or absence of inner ear malformations: Pen‑
dred syndrome (hearing loss associated with goiter) or non‑
syndromic autosomal recessive deafness type 4 (DFNB4).
EVAS is largely associated with allelic variations in the
SLC26A4 gene and to a lesser extent with FOXI and KCNJ10
genes. SLC26A4 gene encodes a hydrophobic membrane
protein called pendrin. This protein manages ion exchange
in many cells, including epithelial cells in the endolymphatic
sac, cochlea, or vestibular labyrinth. There are 200 patho‑
genic/likely pathogenic variants described for SLC26A4 [5].
Bilateral vestibulopathy
Bilateral vestibular hypofunction (BVH), or bilateral vesti‑
bulopathy, is a chronic condition in which both vestibular
organs and VIIIth nerves are damaged, simultaneously or
sequentially. BVH is characterized by unsteadiness, postural
imbalance, oscillopsia and impaired spatial memory and
navigation. Ototoxic drugs, bilateral MD, and meningitis are
the main causes, but the etiology remains unclear in more
than 50% of the patients. A linkage study was carried out
in four families with members affected by BVH, identifying
a region on chromosome 6q which was segregated in these
four families [15]. However, there are no genes identified as
related with BVH.
Cerebellar ataxia, neuronopathy, andvestibular
areexia syndrome (CANVAS)
Cerebellar ataxia, neuropathy and bilateral vestibular are‑
flexia syndrome is a late‑onset, slowly progressive multi‑
system ataxia likely secondary to a neurodegenerative gan‑
glionopathy. In 2016, diagnostic criteria for CANVAS were
proposed [16]. The combination of cerebellar ataxia and
vestibular impairment produces a characteristic oculomotor
sign of impaired visually enhanced vestibulo‑ocular reflex.
However, patients show clinical heterogeneity with overlap‑
ping symptoms with type 3 spinocerebellar ataxia and partial
syndromes. Although most cases are sporadic, the finding of
several affected sibling pairs suggests a recessive disorder
or a dominant inheritance with incomplete penetrance and
variable expressivity [17]. A missense rare variant in the
ELF2 gene has been described in a British CANVAS family
with three patients. This mutation regulated the expression
of ATXN2 and ELOVL5 genes in transduced BE (2)‑M17
cells, suggesting a molecular link with type 2 and type 38
spinocerebellar ataxias [18].
Hereditary sensorineural hearing loss
withvestibular dysfunction
Sensorineural hearing loss (SNHL) refers to a hearing loss
caused by cochlear or auditory nerve damage associated
with a variable vestibular loss. Monogenic syndromic and
non‑syndromic hereditary SNHL includes 15 genes causing
SNHL with vestibular symptoms (Table1). Non‑syndromic
autosomal dominant hearing loss (DFNA) is usually associ‑
ated with postlingual onset SNHL, while prelingual onset is
present with greater frequency in patients with non‑syndro‑
mic autosomal recessive hearing loss (DFNB) or Usher type
1 syndrome (USH1).
Monogenic sensorineural hearing loss
withvestibular involvement
DFNA9
Non‑syndromic autosomal dominant SNHL with vestibular
dysfunction type 9 (DFNA9) is a late‑onset, rare disorder
caused by heterozygous mutations in the COCH (coagula‑
tion factor C homology) gene [19]. This disorder is mostly
shown as a progressive high‑frequency SNHL, and the
phenotype usually includes variable vestibular dysfunc‑
tion (gait imbalance, oscillopsia). Fourteen mutations have
S32 Journal of Neurology (2018) 265 (Suppl 1):S29–S34
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been found in the COCH gene in multiple unrelated families
with DFNA9. Human temporal bone histopathology showed
eosinophilic ground substance deposits in the lateral wall of
the cochlea, possible related to the difficulty of transporta‑
tion and secretion of cochlin in nerve fibers between the
auditory ganglion and sensory epithelium [20].
DFNA11
DFNA11 is a non‑syndromic progressive SNHL with ves‑
tibular dysfunction caused by mutations in the MYO7A gene,
an unconventional myosin involved in the structural organ‑
ization of hair bundles at the sensory hair cells. Patients
show a late‑onset low‑to‑middle frequency hearing loss with
variable vestibular dysfunction. The symptoms progress to
severe cochlear impairment. Mutations in MYO7A have been
described as the main cause of the disorder, as shown in
a family with eight cases with DFNA11 all with the same
deletion in the MYO7A gene [21].
DFNA15
Patients with DFNA15 show an early onset progressive high‑
frequency SNHL associated with vestibular phenotype. It
has been described as caused by several missense mutations
in the POU4F3 gene, a gene encoding a member of POU‑
domain family of transcription factors. In some patients,
vestibular function shows great variability, including cases
from the same family, suggesting that epigenetic factors or
additional genes should be involved in the vestibular phe‑
notype [22].
DFNB103
DFNB103 is a rare autosomal recessive SNHL disorder
with vestibular areflexia described in a Turkish family.
Mutations in the CLIC5 gene have been described as causa‑
tive of this disorder after been observed in a family with
two affected siblings. Studies in mutant mice revealed that
mutation c.96T>A in the CLIC5 gene segregated the hearing
loss phenotype [23].
Familial Meniere disease
Meniere’s disease is a chronic inner ear syndrome charac‑
terized by episodes of vertigo, sensorineural hearing loss,
tinnitus and aural fullness. Its symptoms may overlap with
other diseases such as VM. MD is a rare condition afflict‑
ing approximately 0.5–1 out of 1000 people, most of them
sporadic cases. However, roughly 10% of patients have at
least one other relative (first degree or second degree) with
MD, confirming the familial aggregation of this syndrome.
MD inheritance has been widely discussed, being usually
Table 1 Genes associated in different monogenic and polygenic disorders with sensorineural hearing loss (SNHL) with vestibular phenotype
Type of inheritance: AD, autosomal dominant; AR, autosomal recessive; XLR, X‑linked. SNHL phenotype: HF, high‑frequency hearing loss;
flat, all frequencies affected
Disorder Type of
inherit‑
ance
Gene SNHL phenotype Vestibular phenotype Cell type involved Cell location
DFNA9 AD COCH HF Progressive Supporting cell Extracellular
DFNA11 AD MYO7A Flat Variable Hair cell Cytosol, lysosome, cytoskeleton
DFNA15 AD POU4F3 HF Variable Hair cell Nucleus
DFNB4 AR SLC26A4 Fluctuating Variable Supporting cell Plasma membrane, extracellular
DFNB36 AR ESPN Flat Progressive Hair cell Cytoskeleton
DFNB37 AR MYO6 Flat Poorly characterized Hair cell Plasma membrane, extracellular,
cytoskeleton, nucleus, cytosol
DFNB59 AR PJVK Flat Poorly characterized Hair cell Mitochondrion, nucleus, cytosol
DFNB84A AR PTPRQ Flat Poorly characterized Hair cell Plasma membrane
DFNB103 AR CLIC5 Flat Progressive Hair cell Extracellular, cytoskeleton
USH1 AR MYO7A HF Progressive Hair cell Cytosol, lysosome, cytoskeleton
USH1 AR USH1C HF Progressive Hair cell/supporting cell Cytosol, plasma membrane,
cytoskeleton
USH1 AR CDH23 HF Progressive Hair cell Plasma membrane
USH1 AR PCDH15 HF Progressive Hair cell Plasma membrane, extracellular
USH1 AR USH1G HF Progressive Hair cell Cytoskeleton, cytosol
USH1 AR CIB2 HF Progressive Hair cell Extracellular, cytoskeleton
DFNX2 XLR POU3F4 Flat Poorly characterized Supporting cell Nucleus
S33Journal of Neurology (2018) 265 (Suppl 1):S29–S34
1 3
autosomal dominant, but recessive and mitochondrial inher‑
itance patterns have been observed as well [24].
Some familial studies resulted in the discovery of differ‑
ent genes related to MD. Using WES technology, pathogenic
variants in FAM136 and DTNA genes were detected in a
single family with MD [25]. Other three different families
showed mutations in PRKCB, DPT, and SEMA3D genes.
As shown, genetic heterogeneity between MD families was
observed, as well as incomplete penetrance of the disease in
most families. PRKCB encodes protein kinase C beta type,
a serine‑ and threonine‑specific protein kinase involved in
diverse cellular functions (e.g., apoptosis induction or regu‑
lation of neuronal functions) and it shows tonotopic gene
expression in tectal cells and inner border cells in the mouse
cochlea. The identified heterozygous mutation at position
chr16: 23999898 G>T in the PRKCB gene segregated the
hearing phenotype in the family, and it involves two protein
encoding transcripts, and both are expressed in the human
ear transcriptome [26]. DPT encodes dermatopontin, a non‑
collagenous matrix protein required for cellular adhesion,
and the regulation of TGFβ activity. A missense variant
was identified at chr1: 168665849 G>A in the DPT gene
and it probably produces a functional change in the pro‑
tein sequence. Finally, SEMA3D encodes a member of the
semaphorin III family, and its main function is to guide the
axonal growth cone. A novel missense variant was described
at chr7: 84642128 G>A, modifying an important repeated
domain of this protein [7].
Autoimmune Meniere disease
Several epidemiological studies have found a higher preva‑
lence of autoimmune diseases in patients with both familial
and sporadic MD. Autoimmune MD has been addressed
lately as a separated clinical subgroup with an estimated
prevalence of 7–14 cases in 100,000. We have identified that
the allelic variation in rs4947296, at 6p21.33, is associated
with bilateral MD [OR 2.089 (1.661–2.627); p = 1.39 × 10−9]
and enriched in MD patients with autoimmune comorbidities
[26]. This SNV is a trans‑expression quantitative trait locus
(trans‑eQTL) regulating cellular proliferation in lymphoid
cells through the TWEAK/Fn14 pathway and increasing
NF‑κB‑mediated inflammatory response [27].
Superior canal dehiscence syndrome
Superior canal dehiscence syndrome (SCDS) is a rare condi‑
tion caused by an opening on the bone around the superior
semicircular canal. Hearing loss and vestibular symptoms of
SCDS are usually triggered by loud sounds, pressure stimuli,
or trauma. Its etiology is not clear; however, a recent study
describing 7 SCDS cases in three families provides evi‑
dence of a genetic contribution [28]. Furthermore, studies in
pediatric patients with Usher syndrome and non‑syndromic
deafness associate variants in CDH23 gene as a risk marker
for SCDS [29].
Conclusions
1. Rare allelic variants in coding regions of different genes
are causal in familial vestibular syndromes, including
enlarged vestibular aqueduct syndrome or familial
Meniere’s disease.
2. Common variants in non‑coding regions are considered
regulators of gene expression of multiple physiological
processes in vestibular diseases such as motion sickness
or sporadic Meniere’s disease.
Acknowledgements The authors are supported by Grants from
Meniere’s Society, UK (MS‑2016‑17 Grant), PI17/01644 Grant from
ISCIII by FEDER Funds from EU, H2020‑MSCA‑ITN‑2016‑722046
from EU and Luxembourg National Research Fund (INTER/
Mobility/17/11772209).
Compliance with ethical standards
Conflicts of interest The authors declare no competing conflict of in‑
terest.
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