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Meniere's disease (MD) is an inner ear disorder, characterized by episodes of vertigo associated with sensorineural hearing loss, tinnitus with a multifactorial origin including genetic mutations. This research proposal plans to investigate the genetics underpinnings of Meniere disease in different ethnic groups and compare these data with genes involved in European descendent population. The PhD project goal is to identify new genes in familial MD cases and individuals with early onset by genome sequencing and segregation analysis or rare variants.
A/Professor Jose Lopez Escamez.
North Shore - Kolling Institute of Medical Research
Background
Meniere's disease (MD) is an inflammatory inner ear disorder with a multifactorial origin, including a genetic contribution (1- 3). MD is associated with endolymph accumulation in the inner ear; however, this considered a late event in MD pathophysiology and is associated with hearing loss and duration of the disease (4-6).
Familial aggregation studies have shown that MD has a genetic contribution in European descendent population (7), however there are few studies supporting a familial clustering in East Asian or other ethnicities. Nine genes including FAM136A, DTNA, PRKCB, COCH, DPT, SEMA3D, TECTA, GUSB and SLC6A7 have been associated with autosomal dominant familial MD, whilst 4 genes that have been reported in AR familial MD, including HMX2, LSAMP, OTOG and STRC (8). However, few genes have been reported in multiple families and they encode proteins that links the hair cell stereocilia in the sensory epithelia with the tectorial and otolithic membranes. In this sense, OTOG, MYO7A or TECTA are the main genes associated with familial MD in European population (9-11), but molecular epidemiology studies in other ethnicities are missing.
Aim of the study
The goal of this research proposal is to search for rare variation in coding regions of the genome of patients with MD in different populations in Australia to define the genetic structure of the condition in each population.
Research Methods
Selection of individuals and Inclusion criteria
Patients will be recruited at Healthy Hearing & Balance Care – Meniere’s & Tinnitus clinic in Bondi Junction. For a burden analysis we aim for a minimum of 20 probands and their parents (n (min) = 60 samples). We also plan to recruit families with 2-3 affected individuals for segregation analysis. We will include 10 familial cases and their parents/relatives in first degree (n= 40 samples). Population-specific reference datasets will be used as controls.
Inclusion criteria:
1. Individuals with any ancestry including European (British, Irish, Central and East European), Indian (Hindi, Punjabi) East Asian ancestry (Han Chinese, Zhuang, Hui, Manchu) and criteria A or B.
A. Early-onset sporadic cases (individuals <30 years old) with definite MD diagnosed according to the Barany Society Classification Committee guidelines with a minimum follow-up of 2 years. Both parents must have no familial record of MD.
B. Familial cases (at least 2 individuals with definite MD) and 1 or more relatives without auditory or vestibular symptoms to perform a segregation analysis.
Exclusion criteria: Individuals with other otological conditions including otosclerosis or chronic otitis media.
Genome Sequencing
DNA will be isolated from blood samples and after quality controls, DNA libraries will be prepared by the Truseq DNA PCR free kit (350bp). Genome sequencing will be addressed using the Novaseq 6000 platform (Illumina) with a mean depth of 30X.
Bioinformatic analysis
Pre-process of sequencing data include alignment, sorting and joint calling of the samples to a reference genome. The raw data in fastq files will be analysed and quality valued through FastQC/MultiQC tools. Alignment will be done using BWA mem tool against the last version of the reference genome (GRCh38/hg38). Pre-process and variant calling will be performed using GATK suite, Samtools and Picard. Variant calling will be addressed with different tools: Manta, Delly2, CNVnator for CNV and structural variants, GATK HaplotypeCaller for SNV and indels. Annotation will be carried using Variant Effect Predictor from Ensembl consortium and snpEff tool. Allelic frequencies will be used for variant filtering to target candidate genes. We will phase genotypes of each trio through SHAPEIT2 for parent-of-origin different specific allele discovery. Non-coding region variation will be annotated for regulatory variants in open-chromatin regions for further analyses.
The Meniere disease Neuroscience Laboratory is located at the Kolling Institute. https://kollinginstitute.org.au/menieres-disease-neuroscience-group
Prof. Antonio Lopez Escamez profile
References
1. Lopez-Escamez JA, Carey J, Chung WH, Goebel JA, Magnusson M, Mandalà M, et al. J Vestib Res. (2015) 25:1–7.
2. Espinosa-Sanchez JM, Lopez-Escamez JA. Menière’s disease. In: Furman J, Lempert T, editors. Handbook of Clinical Neurology. Amsterdam: Elsevier B.V. (2016). p. 257–77.
3. Stahle J, Friberg U, Svedberg A. Long-term progression of Meniere's disease. Acta Oto-laryngol Suppl. 1991, 485
4. Rauch SD, Merchant SN, Thedinger BA. Ménière’s syndrome and endolymphatic hydrops: a double-blind temporal bone study. Ann Otol Rhinol Laryngol 1989;98: 873–83.
5. Attyé A, Eliezer M, Medici M, Tropres I, Dumas G, Krainik A, Schmerber S. In vivo imaging of saccular hydrops in humans reflects sensorineural hearing loss rather than Meniere's disease symptoms. Eur Radiol. 2018 Jul;28(7):2916-2922.
6. Perez-Carpena P, Lopez-Escamez JA. Current Understanding and Clinical Management of Meniere’s Disease: A Systematic Review. Semin Neurol. 2020;40(1):138–50.
7. Morrison AW. Anticipation in Menière’s disease. J Laryngol Otol. 1995 Jun 29;109(6):499–502.
8.Parra-Perez AM, Lopez-Escamez JA. Types of Inheritance and Genes Associated with Familial Meniere Disease. J Assoc Res Otolaryngol. 2023 Apr 6. doi: 10.1007/s10162-023-00896-0.
9. Roman-Naranjo P, Gallego-Martinez A, Soto-Varela A, Aran I, Moleon MDC, Espinosa-Sanchez JM, Amor-Dorado JC, Batuecas-Caletrio A, Perez-Vazquez P, Lopez-Escamez JA. Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease. Ear Hear. 2020 Nov/Dec;41(6):1598-1605.
10. Roman-Naranjo P, Moleon MDC, Aran I, Escalera-Balsera A, Soto-Varela A, Bächinger D, Gomez-Fiñana M, Eckhard AH, Lopez-Escamez JA. Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease. Hear Res. 2021 Sep 15;409:108329.
11. Roman-Naranjo P, Parra-Perez AM, Escalera-Balsera A, Soto-Varela A, Gallego-Martinez A, Aran I, Perez-Fernandez N, Bächinger D, Eckhard AH, Gonzalez-Aguado R, Frejo L, Lopez-Escamez JA. Defective α-tectorin may involve tectorial membrane in familial Meniere disease. Clin Transl Med. 2022 Jun;12(6):e829.
The opportunity ID for this research opportunity is 3259