Part One Whole-exome Sequencing Of Discordant Monozygotic Twin Families Identifies Candidate Genes For Otomandibular Dysostosis Part Two Hearing Rehabilitation In Patients With Bilateral Microtia-Atresia

Objective:This study use twin family data to probe genetic factors that contribute to Otomandibular Dysostosis,especially early post-twinning variations that may account for the discordant phenotypes of twin pairs.Methods:We recruited 6 families of monozygotic twins discordant for congenital Otomandibular Dysostosis.The 6 patients shared consistent clinical phenotype of unilateral microtia-atresia.Whole-exome sequencing(WES)was performed for all 6 twins and their parents.Family segregation and multiple other bio informatics methods were applied to find suspicious mutations in all families.Common mutations recurrent in at least two families were identified.Sanger sequencing was applied to validate the variants.Gene Ontology(GO)analysis was performed to identify candidate gene sets and related pathways.Copy number variation(CNVs),linkage analysis,association analysis and machine learning methods were also used to find candidate mutations for the disease.Comparative genomics analysis and structural modeling were conducted to the candidate mutations to analyze their possible roles in the onset of the Otomandibular Dysostosis.Results:The analysis revealed 61 genes with suspicious mutations.Five of them.(HOXA4,MUC6,CHST15,TBX10,AMER1)contain 7 de novo mutations that appear in at least two families.These 5 genes have been reported pathogenic for other diseases.Among them,we identified the mutation in HOXA4(c.920A>C,p.H307P)as the most likely pathogenic variant for microtia-atresia.GO analysis showed 4 gene sets involving 11 pathways that may be related to the pathogenesis of microtia-atresia.CNVs in 3 genes(UGT2B17,OVOS,and KATNAL2)were detected in at least two families.Linkage-analysis showed 13 extra markers for the disease,two of which were revealed by machine learning analysis as candidate genes(FGFR1,EYA1)that may contribute to the disease.Conclusions:Comprehensive genetics and bioinformatics analyses of WES data from 6 families of discordant monozygotic twins with Otomandibular Dysostosis identified multiple candidate genes that may play roles in post-twinning onset of the disease.These findings provide new insights into the pathogenesis of congenital Otomandibular Dysostosis.Objectives:To evaluate the safety and efficacy of auricle reconstruction and bone conduction hearing rehabilitation in patients with bilateral microtia-atresia.Methods:Thirty-two patients,aged 7-27 years,with bilateral microtia-atresia suffering from bilateral conductive hearing loss.All had an upper bone conduction threshold limit of 45 dB HL at frequencies of 0.5-4 kHz.Firstly,hearing thresholds and speech perception in quiet,unaided,using soft-band Bonebridge and implanted Bonebridge,were tested two weeks after the implantation surgery when the Bonebridge was activated.Secondly,hearing thresholds,speech perception and auditory sound localization were tested at least three months after the activation of the Bonebridge under three conditions:unaided,unilateral BHCD(Bonebridge)implantation and bilateral BHCDs(Bonebridge plus contralateral ADHEAR).Patient acceptance ofthese devices in daily life was evaluated by questionnaire.Results:Both the soft-band Bonebridge and implanted Bonebridge can improve the hearing threshold and speech perception in quiet.Compared with unaided,the mean hearing thresholds(0.5,1,2,and 4 kHz)and speech perception following unilateral BCHD and bilateral BCHD attachment were improved significantly(p<0.05 each).The speech perceptin in noise of bilateral BCHD was better than unilateral(p<0.05 each).Markers of directional hearing ability,including percentages of accurate responses,bias angles and RMS errors,were all significantly better following bilateral BCHDs than unilateral BHCD attachment(p<0.05 each).The modified questionnaire revealed high levels of patient satisfaction following use of both unilateral and bilateral devices.Conclusions:The surgical procedure involving auricle reconstruction and Bonebridge implantation was safe and effective for patients with bilateral microtia-atresia,solving both appearance and hearing problems.Sound localization abilities and speech perception in noise were better following bilateral BCHDs than unilateral BCHD attachment.