Study On Clinical Characteristics And Molecular Etiology Of Families With Non-Syndromic Hearing Loss

Hearing loss(HL)is a common clinical sensory impairment disease,which seriously affects people’s quality of life.Genetic factors are the main cause of HL.HL can be classified into syndromic and non-syndromic(>70%)forms based on the presence or absence of distinctive clinical symptoms or signs in other organs aside from hearing loss.Due to the high genetic heterogeneity,hereditary HL often demonstrates that the same phenotype can be caused by different genes or the same gene can cause different HL-related phenotypes,which makes the precision genetic diagnosis of HL challenging.Non-syndromic HL is a classic monogenic disease.With the rapid development of molecular diagnostic technology,more than 100 new HL-associated genes have been identified.However,the etiology of a large number of cases is still unknown.Therefore,the discovery of new genes associating with HL is helpful to clarify the molecular causes of hereditary HL,and genetic diagnosis of hereditary HL is of great significance for understanding the causes and reducing the birth rate of hereditary HL.Part I:Study on clinical characteristics and molecular etiology of a family with autosomal recessive non-syndromic temperature-sensitive auditory neuropathy.Temperature-sensitive auditory neuropathy(TSAN)is a very rare subtype of auditory neuropathy(AN)with elevation of hearing thresholds due to an increase in core body temperature.Here,we report an autosomal recessive TSAN family with four siblings complaining of communication difficulties when febrile and explore the genetic etiology.Audiological tests in febrile episode of these subjects met the classical diagnostic criteria of AN,including mild hearing loss,poor speech discrimination,persistent cochlear microphonic,and absent auditory brainstem response(ABR).However,presence of distortion product otoacoustic emissions(DPOAE)at only few frequencies when febrile,and completely normal hearing,DPOAE and ABR in afebrile episodes is unique compared to all other reported TSAN cases.Further genetic analysis identified a compound heterozygous variant in OTOF gene(otoferlin protein),including one previous reported pathogenic variant c.5098G>C(p.Glu1700Gln)and one novel variant c.4882C>A(p.Prol628Thr).Moreover,neither of both identified variants affects main otoferlin function related C2-domain,of which further functional studies on the exact molecular mechanisms are warranted to elucidate the underlying pathogenic mechanisms.These observations enrich the phenotype and genotype of TSAN and may lay the foundation for the further pathogenesis study.Part Ⅱ:Study on clinical characteristics and identification of new genes in an autosomal dominant non-syndromic HL family.In this part,we studied a three-generation family with 24 members,which was diagnosed as autosomal dominant hereditary non-syndromic HL based on clinical phenotypes and genetic characteristics.Patients in this family had bilateral,symmetric and progressive age-related sensorineural HL with initially only at high frequencies,then at middle-high frequencies and ultimately at all frequencies.Using high-throughput sequencing combined with linkage analysis,we found a suspicious pathogenic varnant KDM4A:c.2961+101G>A which was then ruled out using Minigene technology.In order to find the exact molecular genetic etiology of this family,we applied the third-generation sequencing technology to explore the possible new gene(s)responsible for the hereditary HL in this family.Fortunately,we successfully identified a repeat variation,46630878-46665642(hg19)on chromosome 1,which was confirmed as the possible molecular cause of the family in the present study,however,the underlying pathogenesis needs further study.