Familial Meniere's Disease Research Articles

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9–10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

RotaRod and acoustic startle reflex performance of two potential mouse models for Meniere's disease.

Meniere's disease (MD) is a disorder of the inner ear characterized by chronic episodes of vertigo, tinnitus, increased aural pressure, and sensorineural hearing loss. Causes of MD are unknown, but endolymphatic hydrops is a hallmark. In addition, 5%-15% of MD cases have been identified as familial. Whole-genome sequencing studies of individuals with familial MD identified DTNA and FAM136A as candidate genes for autosomal dominant inheritance of MD. Although the exact roles of these genes in MD are unknown, FAM136A encodes a mitochondrial protein, and DTNA encodes a cytoskeletal protein involved in synapse formation and maintenance, important for maintaining the blood-brain barrier. It is also associated with a particular aquaporin. We tested vestibular and auditory function in dtna and fam136a knockout (KO) mice, using RotaRod and startle reflex-based clicker tests, respectively. Three-factor analysis of variance (ANOVA) results indicated that sex, age, and genotype were significantly correlated with reduced mean latencies to fall ("latencies") for male dtna KO mice, while only age was a significant factor for fam136a KO mice. Fam136a KO mice lost their hearing months before WTs (9-11 months vs. 15-20 months). In male dtna KO mice, divergence in mean latencies compared with other genotypes was first evident at 4months of age, with older males having an even greater decrease. Our results indicate that fam136a gene mutations generate hearing problems, while dtna gene mutations produce balance deficits. Both mouse models should help to elucidate hearing loss and balance-related symptoms associated with MD.

Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease

The MYO7A gene encodes a motor protein with a key role in the organization of stereocilia in auditory and vestibular hair cells. Rare variants in the MYO7A (myosin VIIA) gene may cause autosomal dominant (AD) or autosomal recessive (AR) sensorineural hearing loss (SNHL) accompanied by vestibular dysfunction or retinitis pigmentosa (Usher syndrome type 1B). Familial Meniere's disease (MD) is a rare inner ear syndrome mainly characterized by low-frequency sensorineural hearing loss and episodic vertigo associated with tinnitus. Familial aggregation has been found in 6–8% of sporadic cases, and most of the reported genes were involved in single families. Thus, this study aimed to search for relevant genes not previously linked to familial MD. Through exome sequencing and segregation analysis in 62 MD families, we have found a total of 1 novel and 8 rare heterozygous variants in the MYO7A gene in 9 non-related families. Carriers of rare variants in MYO7A showed autosomal dominant or autosomal recessive SNHL in familial MD. Additionally, some novel and rare variants in other genes involved in the organization of the stereocilia links such as CDH23, PCDH15 or ADGRV1 co-segregated in the same patients. Our findings reveal a co-segregation of rare variants in the MYO7A gene and other structural myosin VIIA binding proteins involved in the tip and ankle links of the hair cell stereocilia. We suggest that recessive digenic inheritance involving these genes could affect the ultrastructure of the stereocilia links in familial MD.

Systematic Review of Sequencing Studies and Gene Expression Profiling in Familial Meniere Disease.

Familial Meniere Disease (FMD) is a rare inner ear disorder characterized by episodic vertigo associated with sensorineural hearing loss, tinnitus and/or aural fullness. We conducted a systematic review to find sequencing studies segregating rare variants in FMD to obtain evidence to support candidate genes for MD. After evaluating the quality of the retrieved records, eight studies were selected to carry out a quantitative synthesis. These articles described 20 single nucleotide variants (SNVs) in 11 genes (FAM136A, DTNA, PRKCB, COCH, DPT, SEMA3D, STRC, HMX2, TMEM55B, OTOG and LSAMP), most of them in singular families—the exception being the OTOG gene. Furthermore, we analyzed the pathogenicity of each SNV and compared its allelic frequency with reference datasets to evaluate its role in the pathogenesis of FMD. By retrieving gene expression data in these genes from different databases, we could classify them according to their gene expression in neural or inner ear tissues. Finally, we evaluated the pattern of inheritance to conclude which genes show an autosomal dominant (AD) or autosomal recessive (AR) inheritance in FMD.

Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease.

Meniere's disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo, and tinnitus. Familial MD has been reported in 6 to 9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D, and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD. Exome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis and a gene burden analysis (GBA) were conducted in the dataset selecting 1 patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls. A total of 5136 single-nucleotide variants in hearing loss genes were considered for single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 rare missense variant in the OTOG gene, suggesting a key role in familial MD. The authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.

Genetic contribution to vestibular diseases.

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 disease. 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.

Genetics of vestibular syndromes.

The increased availability of next generation sequencing has enabled a rapid progress in the discovery of genetic variants associated with vestibular disorders. We have summarized molecular genetics finding in vestibular syndromes during the last 18 months. Genetic studies continue to shed light on the genetic background of vestibular disorders. Novel genes affecting brain development and otolith biogenesis have been associated with motion sickness. Exome sequencing has made possible to identify three rare single nucleotide variants in PRKCB, DPT and SEMA3D linked with familial Meniere disease. Moreover, superior canal dehiscence syndrome might be related with variants in CDH3 gene, by increasing risk of its development. On the other hand, the association between vestibular schwannoma and enlarged vestibular aqueduct with variants in NF2 and SLC26A4, respectively, seems increasingly clear. Finally, the use of mouse models is allowing further progress in the development gene therapy for hearing and vestibular monogenic disorders. Most of episodic or progressive syndromes show familial clustering. A detailed phenotyping with a complete familial history of vestibular symptoms is required to conduct a genetic study. Progress in these studies will allow us to understand diseases mechanisms and improve their current medical treatments.

A pipeline combining multiple strategies for prioritizing heterozygous variants for the identification of candidate genes in exome datasets

BackgroundThe identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets.ResultsPAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM.Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants.ConclusionsOur pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. A cross-sectional study with a two-step cluster analysis. A tertiary referral multicenter study. Nine hundred and eighty-eight adult patients with unilateral MD. best predictors to define clinical subgroups with potential different aetiologies. We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials.

Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere's disease.

Autosomal dominant (AD) familial Meniere's disease (FMD) is a rare disorder involving the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo. Here, we have identified two novel and rare heterozygous variants in the SEMA3D and DPT genes segregating with the complete phenotype that have variable expressivity in two pedigrees with AD-FMD. A detailed characterization of the phenotype within each family illustrates the clinical heterogeneity in the onset and progression of the disease. We also showed the expression of both genes in the human cochlea and performed in silico analyses of these variants. Three-dimensional protein modelling showed changes in the structure of the protein indicating potential physical interactions. These results confirm a genetic heterogeneity in FMD with incomplete penetrance and variable expressivity.

Clinical Subgroups in Bilateral Meniere Disease.

Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD.

A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease.

Meniere's Disease (MD) is a complex disorder associated with an accumulation of endolymph in the membranous labyrinth in the inner ear. It is characterized by recurrent attacks of spontaneous vertigo associated with sensorineural hearing loss (SNHL) and tinnitus. The SNHL usually starts at low and medium frequencies with a variable progression to high frequencies. We identified a novel missense variant in the PRKCB gene in a Spanish family with MD segregating low-to-middle frequency SNHL. Confocal imaging showed strong PKCB II protein labelling in non-sensory cells, the tectal cells and inner border cells of the rat organ of Corti with a tonotopic expression gradient. The PKCB II signal was more pronounced in the apical turn of the cochlea when compared with the middle and basal turns. It was also much higher in cochlear tissue than in vestibular tissue. Taken together, our findings identify PRKCB gene as a novel candidate gene for familial MD and its expression gradient in supporting cells of the organ of Corti deserves attention, given the role of supporting cells in K+ recycling within the endolymph, and its apical turn location may explain the onset of hearing loss at low frequencies in MD.

Genetics of vestibular disorders: pathophysiological insights.

The two most common vestibular disorders are motion sickness and vestibular migraine, affecting 30 and 1–2 % of the population respectively. Both are related to migraine and show a familial trend. Bilateral vestibular hypofunction is a rare condition, and some of patients also present cerebellar ataxia and neuropathy. We present recent advances in the genetics of vestibular disorders with familial aggregation. The clinical heterogeneity observed in different relatives of the same families suggests a variable penetrance and the interaction of several genes in each family. Some Mendelian sensorineural hearing loss also exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. However, the most relevant finding during the past years is the familial clustering observed in Meniere’s disease. By using whole exome sequencing and combining bioinformatics tools, novel variants in DTNA and FAM136A genes have been identified in familial Meniere’s disease, and this genomic strategy will facilitate the discovery of the genetic basis of familial vestibular disorders.

Cinical and genetic characteristics of familial Meniere's disease: three families report

To investigate the clinical and genetic characteristics of three Chinese Meniere's disease (MD) families and decipher the mechanism of MD further. Personal and family medical evidence of hearing loss, vestibular symptoms, and other clinical abnormalities of the participants were identified, clinical and genetic features were analyzed. Targeted 307 genes capture and high-throughput sequencing were performed on the two ascertained members of family 1007184. Eight patients from these three families showed post-lingual sensorineural hearing loss, six women and two men were involved. Age of onset in these affected members concentrated in the middle age, with the average age of 39.3 years old. Among them, patients from 1407278 were accompanied by migraine. All of the three probands presented as recurrent vertigo firstly, and then fluctuated hearing loss showed up, accompanying by tinnitus and ear fullness feeling. The hearing loss manifested as late-onset, low frequency-involved pattern, with subsequent gradual progression from moderate to severe level. Some of the patients progressed to severe level involving all frequencies at higher ages. In addition, most of the cases showed revitalization. Four cases received vestibular function tests, three of which had varying dysfunction of vestibular function, while the other one had normal vestibular function. Patients who had abnormal vestibular function showed much more severe hearing impairment. The three-generation family 1007193 had an autosomal recessive genetic characteristics, family 1007184 showed autosomal dominant inheritance of characteristics, family 1407278 were either autosomal dominant or X-linked dominant pattern. Through target genes capture high-throughput sequencing technology, we identified two candidate variants in the two members of family 1007184, named c. 2057G>A in EGFLAM and c. 1961C>T in ITGA8. Meniere's disease has some genetic and familial aggregation in Chinese population, but its complex genetic pathogenic mechanisms need further study.

Genetic aspects and clinical characteristics of familial Meniere's disease in a South Korean population.

This study was undertaken to investigate the prevalence, inheritance patterns, and clinical characteristics of familial Meniere's disease (MD) in a South Korean population. Direct interviews, telephone interviews, and reviews of the medical records of definite Meniere's disease patients and their families. Direct and telephone interviews were performed for 286 definite MD patients and their family members who were suspected of having MD. The diagnosis of MD in family members was made by obtaining a detailed history, performing basic neurotological examinations and reviewing hearing test results. The clinical characteristics as well as the prevalence and inheritance patterns of familial MD were analyzed. The prevalence of familial Meniere-like syndrome (at least one family member with definite MD and other members with probable MD) and definite familial MD (two or more family members with definite Meniere's disease) were 9.8% and 6.3%, respectively, and the most common inheritance pattern was autosomal dominant with incomplete penetrance. The significant clinical characteristics of familial cases were an early disease onset and a higher prevalence of migraines. This is the first report describing the genetic aspects of MD in a single large Asian population. The prevalence of definite familial MD was 6.3% with an incomplete autosomal dominant inheritance pattern in most cases. Early-onset age and a high prevalence of migraines were significant clinical features of familial MD in this South Korean population. These data could provide a basis for the analysis of the genetic mechanism of familial MD in Asian populations. 4.

Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease.

Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD.

Familial clustering and genetic heterogeneity in Meniere's disease

The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology-Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs ) and offspring (λo ) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16-48 and 4-12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.

High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland

Objective of this study was to systematically investigate the family histories of a large set of patients affected with Meniere's disease to determine the prevalence of familial MD and Meniere-like symptoms in their families. All 640 patients treated at the Oulu University Hospital and Kainuu Central Hospitals during 2005–2010 for Meniere's disease were selected as the initial study population. A postal family history survey was sent to all subjects. Hospital records of all patients were studied to confirm diagnosis and sufficient differential diagnosis. All patients that revealed a positive family history of Meniere's disease or Meniere-like symptoms were phone interviewed and the probability of Meniere's disease in a relative was estimated on a three level scale: probable, possible or unlikely. Affected family members of the patients were recruited to the study if possible. Familial Meniere's disease could be confirmed in 9.3% of patients, but 32.7% patients reported Meniere-like symptoms in their family. It was not possible to confirm all cases, but a family history of Meniere's disease was convincing (confirmed or probable) in 23.4% of the patients. Genetic factors are significant in the development of Meniere's disease.

Finnish familial Meniere disease is not linked to chromosome 12p12.3, and anticipation and cosegregation with migraine are not common findings

PurposeTo study the inheritance and characteristics of familial Meniere disease in Finland and genetic linkage to the previously proposed locus on chromosome 12p12.3. MethodsSixteen Meniere families recruited from Kainuu Central Hospital and Helsinki and Oulu University Hospitals in the period 2001–2004 were reevaluated in 2009 using hospital records and mailed questionnaire forms. Ten highly polymorphic microsatellite markers were selected from the area of chromosome 12p12.3 and studied for linkage using the GENEHUNTER protocol. ResultsThe families showed autosomal dominant inheritance without cosegregation with migraine. Anticipation was seen only in one family, and in the rest of the families, the age of onset varied randomly among generations and individuals. The severity of the disease was not related to descending generations. None of the maximum logarithm of odds (LOD)/heterogeneity LOD scores in the analysis of chromosome 12p12.3 in Finnish Meniere families reached a significant value of 3.0 (maximum cumulative LOD score: −7.29, heterogeneity LOD: −0.95, α = 0.4). ConclusionsFamilies affected by Meniere disease are highly heterogeneous. Migraine, age at onset, anticipation, or penetrance was not a shared feature. The findings support the multifactorial nature of the disease and indicate that genetic heterogeneity exists within familial Meniere disease.

Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association

Meniere's disease (MD) is a disorder of the inner ear characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. Most MD cases are sporadic, but 5-15% of patients are familial following an autosomal dominant mode of inheritance with incomplete penetrance. We have previously identified a candidate gene region for MD on chromosome 12p12.3 using linkage analysis. We genotyped 15 Swedish families segregating familial MD (FMD) to further clarify the role of chromosome 12p in a larger cohort of families. Highly polymorphic marker loci were analyzed over the 16-Mb candidate region in affected and healthy family members as well as in control subjects. The results revealed allelic association between FMD and several individual polymorphic marker alleles and single-nucleotide polymorphisms. Moreover, a common three-marker haplotype spanning 1.48 Mb co-segregates with FMD in 60% of the families investigated, forming the core of a possible ancestral haplotype associated with FMD in Sweden.