Genetic Study Of Two Aural Vertigo Diseases

Vertigo is a motion or position illusion caused by spatial orientation disorder, with the rotation feeling of surrounding environment and/or themselves, or swing instability, shaking, top-heavy sense. The vast majority of people have experienced vertigo in their lives, especially in the elderly over 60 years, with the incidence of up to 30%. According to statistics, after headache, vertigo is the second most complained symptom in the hospital outpatient, accounting for 5%,15% and 15% of outpatients in medical clinic, otolaryngology clinic and neurology and orthopedic clinic, respectively. Vertigo can be divided into genuine and pseudo vertigo. Genuine vertigo is caused by diseases of vision, proprioception, or the vestibular system, with a clear sense of rotation of surrounding objects or themselves. Pseudo vertigo is often caused by systematic diseases, such as cardiovascular disease, cerebrovascular disease, endocrine disease, anemia, uremia, drug poisoning and neurosis, having varying severity of dizziness and fluttering swing feeling, instead of clear sensation of rotation.Due to the limitations of inspection methods and the complexity and multi-disciplinary of the vertigo disease, the progress of the vertigo diseases studies was very slowly, especially mechanism research. In recent years, a hot wave of vertigo related diseases research has been raised both at home and abroad. On the other hand, the rapid progress of high-throughput sequencing technologies and advanced bio informatics analysis began the blowout growth of disease-causing genes identification. Based on the valuable genetic resources, this study adopted advanced strategies in genetic research, such as targeted region capture, exome sequencing, bio informatics analysis and mass spectrum analysis, to summary the phenotype character of Meniere disease (MD) families and sudden deafness with vertigo patients, and to explore the susceptibility genes of two aural vertigo diseases, laying a foundation for deciphering genetic mechanism of aural vertigo. The study includes the following two parts:Part one:Study of phenotype and related genes of Meniere’s disease families.In this part, clinical data and genetic resources of three MD families were collected. 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. High-throughput sequencing and bioinformatics analysis were performed on the families members, analyzing the genetic screening results and explore its genetic characteristics.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 39.33 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. 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 later ages. In addition, most of the cases showed revitalization. Four cases had 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 and 1407278 showed autosomal dominant inheritance of characteristics. Targeted capture and high-throughput sequencing were performed on eight individuals of the three families, including four MD patients, two migraine with deafness patients and two unaffected control. The obtained data was compared with the human genome database to screen rare variants, then the SNP and Indel were performed function prediction. The results were as follows:two candidate variants in the two members of family 1007184, namely c.2057G>A in EGFLAM and C.196C>T in ITGA8 were identified, verified by mass spectrum analysis and Sanger sequencing, with the wild type of all of the one hundred normal controls. No candidate pathogenic variation was identified in family 1007193 and 1407278. Therefore, we believe Meniere’s disease has some genetic and familial aggregation of population in China, but its complex genetic mechanism, pending further study. Mcniere’s disease has some genetic and familial aggregation in Chinese population, but its complex genetic pathogenic mechanisms need further study.Part two:Study of clinical characteristics and related genetic research of sudden hearing loss patients with vertigoIn this part, we retrospectively analyzed the clinical characteristics of 240 patients diagnosed as sudden sensorineural hearing loss (SSHL) with vertigo, treated in the Chinese PLA General Hospital from July 2008 to August 2012. Various factors affecting the therapeutic effects were analyzed, such as audiological features, vestibular function tests, genders, audiograms, lasting before seeing a doctor, courses of vertigo and vascular factors.51 cases of unilateral sudden deafness with vertigo patients and2 cases of bilateral sudden deafness with vertigo patients were performed high-throughput sequencing studies to reveal the molecular pathogenesis of sudden deafness from a genomics perspective and discover molecular markers associated with the onset of deafness, and then supply prevention to high-risk populations, classify disease according to accurate etiology, choose a much more precision therapy.Among the contemporaneous SSHL patients (873 cases), the cases with vertigo accounted for 27.49%(240/873). Among the 240 patients with vertigo, the cases with different hearing impaired degree of mild, moderate, severe and profound were 30,13, 28 and 34 respectively, primarily by the profound cases. Detailed vestibular function tests were performed in 97 patients, with 54 cases having unilateral vestibular disfunction and 43 patients having normal vestibular function, among which 23 cases were diagnosed as benign paroxymal positional vertigo (BBPV). The relationship between vestibular function and different hearing impaired degrees or various audiogram types had no statistically significant difference.219 cases had detailed records of the onset time of cochlear and vestibular symptoms, including 122 patients with cochlear symptoms and dizziness occurring simultaneously. After standardized drug treatment, the total effective rate was 46.67%, with 17 cases recovery,34 cases excellent better,61 cases better and 128 cases poor respectively. Statistical analysis showed that different genders, audiogram types, vertigo courses of time, the results of vestibular function and neck vascular ultrasounds were not related to the curative effects, while the treatment time after onset was significantly associated with treatment effects. Conclusion SSHL with vertigo has a high incidence, primarily single side affected, with relatively severe hearing impairment, and total deafness and downslope hearing curve mainly. Vestibular function can be normal or low in SSHL patients with vertigo, with a higher incidence of BPPV. Vestibular and cochlear symptoms occur simultaneously in more than half of the patients. The detection rate of vestibular dysfunction gradually increased, as the degree of hearing loss increased, without statistical significance although. The therapeutic effects of sudden hearing loss with vertigo cases have no relationship with dizziness duration or vestibular function, while the disease course plays an important role in treatment.Among the 240 cases of sudden deafness with vertigo,51 samples of unilateral sudden deafness and 2 cases of bilateral deafness were performed high-throughput sequencing to explore the genetic mechanism, analyzing candidate gene variations. For the 51 unilateral sudden deafness with vertigo cases, including 2 cases with low-mid frequency hearing impairment,18 cases with mid-high frequency hearing loss,11 cases with flat-type hearing loss, and 20 cases with all frequency hearing loss. Among the 51 cases, eight GJB2 heterozygous variations were identified, with the incidence of 15.69%,1 GJB3 heterozygous variation was identified, with the incidence of 1.96%,2 COCH heterozygous variations were identified, with the incidence of 3.92%,5 SLC26A4 heterozygous variations were identified, with the incidence of 27.45% and no vestibular aqueduct were found through temporal bone CT in these cases,5 CDH23 and 5 OTOF heterozygous variations were identified respectively, with the incidence of 27.45%,1 SLC17A8 heterozygous variation was identified, with the incidence of 1.96%,2 KCNE1 heterozygous variations were identified, with the incidence of 3.92%, no mitochondrial variation was identified. Among the8 patient with GJB2 heterozygous mutation,7 cases were profound hearing loss, one case was severe deafness, and seven of these eight cases had no effective treatment. For the two cases of bilateral sudden deafness with vertigo, with simultaneously onset and varying degrees of sudden hearing loss, no clear candidate variation was found.Feature of this study:this is the first collection of clinical data and genetic resources of Chinese familial Meniere’s disease, with three MD families collected, and detailed audiology and vestibular function tests were performed; and in this study, we applied new generation sequencing technology and advanced bioinformatics analysis tools on analyzing the results of genetic screening of MD families to explore their genetic characteristics. For the genetic research on SSHL, though began earlier, most studies focused on a single candidate gene screening. Based on the targeted deafness and hearing-related genes capture and high-throughput sequencing, we explored the possible molecular mark of SSHL with vertigo preliminary.