Clinical And Genetic Analysis Of Rare Syndromic Hearing Loss

Objective:Multiple synostoses syndrome-1（SYNS1;OMIM#186500）is a rare autosomal dominant disorder characterized by multiple joint fusions,conductive hearing loss,and characteristic facial features.Perrault syndrome-4（PRLTS4;OMIM#615300）is a rare autosomal recessive disorder characterized by premature ovarian insufficiency（POI）in females,and sensorineural hearing loss（SNHL）in both genders.Treacher Collins syndrome-1（TCS1;OMIM#154500）is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia and conductive hearing loss.Here,we report a Chinese pedigree with SYNS1,a Chinese pedigree with PRLTS4,and 5 cases of TCS1 in Chinese patients.Besides,the characteristics of clinical phenotypes and mutations are studied.Methods:We evaluated audiological,radiological,endocrine,and ultrasound examinations.Whole-exome sequencing（WES）was performed to examine the genetics of the diseases,and Sanger sequencing was used to confirm the identified variants.We reviewed the literature to do the retrospective analysis of the pathogenesis,genotype-phenotype correlation,treatment,and prevention of diseases.Results:Medical WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene,c.554C>G（p.Ser185Cys;NM₀05450.4）,co-segregated in the SYNS1 family.Sanger sequencing revealed that c.554C>G（p.Ser185Cys）was inherited from the proband’s father.Neither her mother nor her grandmother carried this mutation.It was absent in the gnomAD population database and was classified as likely pathogenic by the American College of Medical Genetics and Genomics（ACMG）guidelines.WES and bioinformatic analysis revealed compound heterozygous mutations in the LARS2 gene,c.880G>A（p.Glu294Lys;NM₀15340.3）and c.2108T>C（p.Ile703Thr）which is a novel missense mutation,co-segregated in the PRLTS4 family.Sanger sequencing revealed that c.880G>A（p.Glu294Lys）was inherited from the proband’s mother and c.2108T>C（p.Ile703Thr）was inherited from her father.Her younger brother carried neither of these two variants.The variant c.2108T>C（p.Ile703Thr）was absent in the gnomAD population database and was classified as likely pathogenic by the ACMG guidelines.In five Chinese TCS1 patients,WES revealed a novel insertion of c.939₉40insA（p.Gly314Argfs*35;NM₀01135243.1）,a novel deletion of c.1766delC（p.Pro589Leufs*7）,two previously reported insertions of c.1999₂000insC（p.Arg667Profs*31）and c.4218₄219insG（p.Ser1407Valfs*23）,and one previously reported deletion of c.4369₄373delAAGAA（p.Lys1457Glufs*12）in the TCOF1 gene.Conclusion:This study identified the genetics of the diseases and expanded the mutation spectrum of the related genes.It reflects the cross integration of multiple disciplines.WES plays an important role in early diagnosis of syndromic hearing loss and clinical genetic evaluation is essential to guide prevention.