Genetics of vestibular syndromes

Roman‐Naranjo, Pablo; Gallego‐Martinez, Alvaro; Lopez-Escamez, José A.

doi:10.1097/wco.0000000000000519

Cited by 22 publications

(15 citation statements)

References 60 publications

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“…Over the last 20 years, many candidate genes have been proposed for MD based on the so-called "common diseasecommon variants" paradigm that prevailed in complex disease genetic studies (8)(9)(10). It was thought that the common variants may lead to genetic susceptibility to complex polygenic disease (43).…”

Section: Discussionmentioning

confidence: 99%

“…Most MD cases are sporadic, but familial MD is observed in 8-10% of sporadic cases, suggesting genetic susceptibility to the development of MD (3)(4)(5). To search a candidate gene associated with MD, many approaches including linkage analysis, case-control study or the sequencing of selected genes have been previously used (6)(7)(8)(9)(10). A variety of common single nucleotide polymorphisms (SNPs) have been meaningfully detected in patients with MD (Supplementary Table 1).…”

Section: Introductionmentioning

confidence: 99%

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Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Shin

Kim

et al. 2020

Front. Neurol.

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Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD. Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency >0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling. Results: The average read depth for the targeted regions was 1446.3-fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n = 100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis. Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Shin

Kim

et al. 2020

Front. Neurol.

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“…Epidemiological studies indicate that MD is most common in European population, suggesting a genetic predisposition (Ohmen et al 2013). Although the majority of MD patients are considered sporadic (Frejo et al 2016; Frejo et al 2017), familial clustering has been reported in 8-9% of sporadic cases in the European descendent (Requena et al 2014), and in 6% of Korean population (Lee et al 2015), which also supports a genetic contribution to the disease (Roman-Naranjo et al 2017). MD shows a wide range of phenotypic variations among patients, even within the same families (Lee et al 2015b), and it is commonly associated with migraine and systemic autoimmune disorders (Tyrrell et al 2014; Cha et al 2008).…”

Section: Introductionmentioning

confidence: 98%

Rare Variants in theOTOGGene Are a Frequent Cause of Familial Meniere’s Disease

Roman‐Naranjo

Gallego‐Martinez

Soto-Varela

et al. 2019

Preprint

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1Objectives: Meniere's disease (MD) is a rare inner ear disorder characterized by 3 2 sensorineural hearing loss, episodic vertigo and tinnitus. Familial MD has been reported 3 3 in 6-9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, 3 4 SEMA3D and DPT have been involved in single families, suggesting genetic 3 5 heterogeneity. In this study, the authors recruited 46 families with MD to search for 3 6 relevant candidate genes for hearing loss in familial MD. 3 7 Design: Exome sequencing data from MD patients were analyzed to search for rare 3 8 variants in hearing loss genes in a case-control study. A total of 109 patients with MD 3 9 (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the 4 0 diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The 4 1 allelic frequencies of rare variants in hearing loss genes were calculated in individuals 4 2 with familial MD. A single rare variant analysis (SRVA) and a gene burden analysis 4 3 (GBA) were conducted in the dataset selecting one patient from each family. Allelic 4 4frequencies from European and Spanish reference datasets were used as controls. 4 5 Results: A total of 5136 single nucleotide variants in hearing loss genes were 4 6 considered for SRVA in familial MD cases, but only one heterozygous variant in the 4 7 OTOG gene (rs552304627) was found in two unrelated families. The GBA found an 4 8 enrichment of rare missense variants in the OTOG gene in familial MD. So, 15/46 4 9 * This novel variant was not included in the gene burden analysis. Abbreviations: MAF FMD, minor allele frequency in familial MD; MAF ALL MD, minor allele frequency in all familial and non-familial MD cases ; NFE, Minor allele frequency in non-Finnish European population; CSVS, Collaborative Spanish Variant Server; Abf, alpha-L-arabinofuranosidase B domain; CADD, Combined Annotation Dependent Depletion Score; CT: cysteine knot domain; vWD, von Willebrand factor type D domain.

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“…Most cases of VM are considered sporadic, but familial aggregation of VM with autosomal-dominant inheritance has been described in several families, supporting a genetic background for the condition (3,4). Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with a genetic predisposition for migraine with or without aura (5,6).…”

Section: Introductionmentioning

confidence: 99%

TRPM7 as a Candidate Gene for Vestibular Migraine

Shin

Cho

et al. 2020

Front. Neurol.

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Objectives: Vestibular migraine (VM) is a common vestibular disorder, and familial aggregation of VM with autosomal-dominant inheritance has been described, which supports a genetic background. This study aimed to describe the clinical phenotype of a family with VM, and identify a candidate gene for VM. Methods: We recruited six individuals (four affected and two unaffected) from three consecutive generations of a Korean family with VM, and performed whole-exome sequencing to search for candidate genes. Results: All affected individuals presented with recurrent vertigo, headache, and nausea/vomiting that fulfilled the diagnostic criteria of VM. Two individuals also experienced transient hemiparesis or dysarthria during the episodes. The symptoms were triggered by physical or emotional stress. Interictal examinations showed uni-or bi-directional horizontal gaze-evoked nystagmus in three of the individuals. They had no causative mutations in genes causing familial hemiplegic migraine or episodic ataxia. Through whole-exome sequencing from three affected individuals, we identified a nonsense mutation c.3526C>T in TRPM7 that encodes a cation channel selective to Ca 2+ and Mg 2+. Conclusions: Alterations in intracellular Ca 2+ and Mg 2+ homeostasis by TRPM7 mutation may contribute to the development of the VM phenotype. Our result suggest that TRPM7 is a novel candidate gene for VM.

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Genetics of vestibular syndromes

Cited by 22 publications

References 60 publications

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Rare Variants in theOTOGGene Are a Frequent Cause of Familial Meniere’s Disease

TRPM7 as a Candidate Gene for Vestibular Migraine

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