Phenotypic And Genotypic Characteristics Of Patients With Age-Related Hearing Loss

Age-related hearing loss（ARHL）is caused by a combination of aging,environmental and genetic factors.The disease not only affects the ability of elderly patients to communicate with others,but also has a significant impact on their daily lives and imposes a heavy economic burden on society.Therefore,early detection of ARHL is crucial.Currently,methods and techniques for genetic studies of congenital or early-onset hearing loss are quite well established,and relatively little research has been done on ARHL.In order to understand the epidemiological characteristics of ARHL and the role of genetic factors in the development of ARHL,this study firstly analyzed the pure-tone hearing data of a large sample ofARHL patients from multiple regions retrospectively to explore the population distribution pattern and hearing loss characteristics of ARHL patients and to provide a traceable pattern for the early detection of ARHL.Second,this study will also explore how genetic factors play their role in the development and progression ofA RHL.The personal history,family history,hearing test results and blood samples ofARHL patients who visited at the General Hospital of the Chinese People’s Liberation Army between 2021 and 2022 were collected,and the patients were divided into sporadic ARHL patients and familial ARHL patients,and ARHL patients were screened for suspected causative genes in combination with audiometric testing.On this basis,we screened the genes for ultrarare variant loci,analyzed the association between phenotype and genotype using the causal relationship between ultrarare variants and phenotype,and searched for pathogenic genes that may cause ARHL,with the aim of finding the genetic characteristics of ARHL and providing reference opinions for early clinical detection and intervention.Part Ⅰ Characterization of Hearing Loss in Patients with Multi-Regional Age-Related Hearing LossObjective The hearing data of patients with age-related hearing loss in a multi-geographic scope were analyzed to explore the characteristics and epidemiological features of age-related hearing loss in China in terms of diminished auditory system function.Methods Basic information and audiological data of a large sample of ARHL patients from multiple regions were collected,and statistical analysis was performed using SPSS 26.0.statistical software,and statistical methods such as independent sample t-test,one-way analysis of variance（ANOVA）,and correlation analysis were used to understand the degree of each frequency threshold and hearing loss in ARHL patients,the differences between different ages,ear categories,and genders in ARHL patients,and the age factors in the occurrence and development of ARHL.Results 1.A total of 6484 patients were included in the total sample and divided into 2 groups:less than or equal to 74 years old for the younger elderly group（83.4%）and older than 74 years old for the elderly group（16.6%）;there were more female patients（61.5%）than male（38.5%）.2.By plotting box plots,it can be seen that there are more abnormal values at low thresholds for each frequency of pure tone audiometry in ARHL patients;plotting box plots for each frequency threshold of pure tone audiometry in people aged 80 years and above reveals that there are very few abnormal values in people aged 80 years and above.3.The analysis of pure tone audiometry thresholds for each frequency in the total population revealed that the thresholds from 250Hz～8 kHz were distributed from positive skewed distribution,gradually normal distribution to negative skewed distribution in high frequencies,indicating a mild degree of hearing loss in low frequencies and a heavy degree of hearing loss in high frequencies.4.By independent sample t-test,it was found that the pure tone audiometry thresholds for all frequencies were significantly lower in the young elderly group than in the elderly group,and the threshold difference between the two groups of patients reached the maximum at 8 kHz,about 16 dB（P<0.001）.5.The degree of high frequency hearing loss was greater in males than in females.In the young elderly group,the comparison of male and female thresholds was statistically significant（P<0.05）in the left and right ears from 500Hz～8 kHz,with the largest difference between male and female thresholds at 4 kHz,reaching 10.9 dB.The difference between male and female in the elderly group was smaller,with the largest difference between male and female thresholds at 4 kHz,reaching 6.5 dB.6.The total population was divided into 8 groups using 3 years as an age group,and ANOVA analysis was performed on the thresholds of each frequency in both ears of each group,and it was found that the differe nces in thresholds were small and not statistically different at 76-81 years（P>0.05）.7.There was a significant difference between the right and left ear PTA（P<0.001）,and the right ear PTA was slightly lower than the left ear in all 8 groups of patients,but not statistically significant between groups 5 and 8.8.A weak positive correlation between age and each frequency threshold was found by correlation analysis（P<0.001,r>0）.Conclusion 1.The ARHL consultation population is predominantly 74 years old and younger,with females accounting for a large proportion of the total population,which may be related to the need for hearing improvement,mobility and the greater vulnerability of females to tinnitus.2.The audiometric configuration of ARHL patients has the characteristics of high-frequency decline,indicating that hearing loss starts from high frequency first,and the overall hearing characteristics show bilateral symmetrical high-frequency decline type hearing loss.3.The degree of hearing loss is less in females than in males,but the difference between the sexes at high frequencies decreases with increasing age.4.The rate of hearing loss slows down in the age group of 76 to 81 years.5.Patients with ARHL may also maintain right ear dominance.Part Ⅱ Characterization of the Genetic Profile of Patients with Age-Related Hearing Loss Objective To characterize the phenotype and genotype of ARHL patients by audiometric testing and genetic testing for hereditary deafness,and to search for possible causative genes in ARHL patients.Methods A total of 36 patients who were diagnosed with ARHL between 2021 and 2022 at the General Hospital of the Chinese People’s Liberation Army were recruited to collect personal information,current medical history,past history,family history and other relevant information as well as venous blood samples for pure tone audiometry and genetic testing for hereditary deafness.Ultra rare variant loci were screened,benign/probably benign genetic variant loci were excluded by OMIM,ClinVar website,and the function of the screened ultra rare variant loci was predicted by using protein function prediction software.Results 1.The sample of this study included 20 females and 16 males;the mean age was 68.9± 7.5 years,with a minimum age of 61.years and a maximum age of 93 years;the mean age of onset of hearing loss was 63.8 ± 8.3 years,with a minimum age of 45 years.2.Hearing loss degree:According to WHO hearing loss degree classification standard,the largest proportion of patients with mild and moderate hearing loss（75%）;hearing loss of moderately severe and severe accounted for 22.2%,and there were no patients with profound hearing loss and complete hearing loss.Audiometric configuration included declining（91.6%）,rising（2.8%）,and flat（5.6%）type.3.Underlying diseases:Among the 36 patients,23（78.2%）had underlying diseases（including diabetes,hypertension,hyperlipidemia,coronary artery disease,etc.）.4.A total of 23 patients with sporadic ARHL had genetic test results with variants detected associated with the chief complaint in 16 patients（70.8%）;patients with familial ARHL involved 13 prevalent individuals from 13 families and genetic test results with variants detected associated with the chief complaint in 10 patients（77%）.Among them,GJB2 was the most common variant gene,detected 5 times in this study sample,c.299₃00delAT,c.235delC and c.109G>A,respectively.5.Ultra rare variant loci:A total of 8 patients were screened for genetically ultra rare variant loci.11 URVs involving 9 different genes were screened,including DSPP,CHD7,TNC,DMXL2,MYO7A,DIAPH3,COL11A2,TRRAP,and ADGRV1 genes.Conclusions 1.The detection rate of genetic variants in sporadic and familial ARHL in this study was around 70%,indicating that genetic factors have some weight in the development of ARHL,and the suspected causative genes of ARHL detected are also genes that cause delayed deafness,such as MYO7A and TMC1 genes.2.By screening for ultra rare variants in genes,we found some genes that may be associated with ARHL,such as TRRAP,MYO7A,PTPRQ,COCH and DMXL2 genes,increasing the spectrum of ARHL candidate gene variants.3.Screening for ultra rare variants of genes is necessary to help us avoid missing potentially pathogenic variants and is important for us to identify the risk of developing ARHL.