Analysis Of Clinical Features And Genetic Diagnosis Of Three Families With Waardengburg Syndrome

Objective:By studying 3 families of Waardenburg syndrome（Waardenburg syndrome,WS）,analyzing their genetic and clinical characteristics,identifying the pathogenic genes,exploring possible molecular pathogenic mechanisms,and providing a theoretical basis for the prevention and treatment of hereditary deafness.Methods:1.Conduct medical history collection,physical examination,audiological evaluation,and CT examination of the temporal bones for the probands and their families of 3 families,draw family atlas,and make clinical diagnosis.2.Collect peripheral blood samples from 3 families,extract DNA,and perform high-throughput sequencing of 406 deafness genes in probands in the family.Probands and their another families are verified by Sanger sequencing.3.Use UGENE to analyze the gene sequence conservation of mutations located on exons,SIFT,PROVEAN,Mutation Taster,GERP,PolyPhen2,REVEL and other software to analyze the pathogenicity of missense and splicing mutant genes,and use Swiss-model right and wrong The three-dimensional protein structure of the sense mutant gene is predicted,and the structure before and after the mutation is compared and analyzed.Results:Proband 1 has a heterochromatic iris in the right eye,widened internal canthus,extremely severe sensorineural hearing loss on both sides,and his father has heterochromatic iris in the right eye and moderate sensorineural hearing loss on both sides.Genetic testing.The c.602C>G（p.Ser201*）mutation in exon 5 of 1PAX3 in the proband is a nonsense mutation.As a result,the amino acid at position 201 of the encoded protein was changed from serine to a stop codon,and Sanger verified that the father carried the mutation.This locus is highly conserved among multiple species.The mutation at this locus is not included in the database.It is a new mutation.Based on the above results,the proband 1 and father are diagnosed as WS1;the proband 2 has bright blue irises in both eyes and bilateral polarities.Severe sensorineural hearing loss,parents have no special phenotype,proband 2 gene test found that SOXIO gene 4 intron c.698-2A>C heterozygous mutation,resulting in amino acid splicing mutation,parents were not found by sanger sequencing The mutation at this site,this mutation is a spontaneous mutation.SIFT,PolyPhen₂,MutationTaster,GERP++,and REVEL respectively predict the consequences of the mutation at this locus as unknown,unknown,harmful,harmful,and unknown.Proband 2 is diagnosed as WS2 based on the above results;proband 3 has bright blue iris in both eyes,double Patients with extremely severe sensorineural hearing loss,parents without the above phenotype,the proband 3 gene detected a heterozygous mutation in SOX10 gene exon 2c.346C>G（p.Q116E）,resulting in amino acid missense mutations,parents Sanger sequencing did not find a mutation at this site,this mutation is a spontaneous mutation.Sequence analysis This site is highly conserved among multiple species.SIFT,PolyPhen₂,MutationTaster,GERP++,and REVEL respectively predict the consequences of the mutation at this site as harmful,harmful,harmful,harmful,and harmful.The Swiss-model three-dimensional structure prediction shows that the three-dimensional structure of the protein changes after amino acid changes.According to clinical phenotype and genetic testing As a result,proband 3 was diagnosed with WS2.Conclusions:1.This study found PAX3c.602C>G（p.Ser201*）is a new mutation,SOX10c.698-2A>C and SOX10c.346C>G（p.Q116E）is a spontaneous mutation,and the above gene mutation is preliminarily identified as the molecular cause of WS.The discovery of these sites enriched the gene mutation spectrum of WS.2.The phenotype of WS is very different,and the appearance is not complete.The role of genetic testing in diagnosis should be paid attention to.3.Through the analysis of the clinical characteristics and molecular etiology of WS,it can better assist in clinical diagnosis,provide theoretical support for clinical treatment and genetic counseling,and strengthen the prevention and treatment of hereditary deafness.