Research On A Marfan Syndrome Family Containing Members With Waardenburg Syndrome And Identification Of Disease-causing Mutations

Purpose: Waardenburg syndrome(WS)and Marfan syndrome(MFS)are both syndromic genetic diseases involving ocular abnormalities.The purpose of this study was to collect the clinical characteristics of this family in detail and identify the pathogenic mutations.Methods: Comprehensive ophthalmic examinations and general examinations were undertaken and peripheral blood samples were collected for DNA extraction from all of the subjects(family members and healthy control group members).Whole exome sequencing was conducted in tow selected family member.Sequencing data were filtered step by step and analyzed and predicted by bioinformatics to screen out candidate variants.The identified candidate mutations were validated by PCR-Sanger sequencing and co-segregation analysis.The segregating variant was analyzed in 200 normal controls.Results: Seven family members participated in the study ranged in age from 10 to 37 years old.There were 5 MFS patients(2 males,3 females),1 suspected MFS patient(female),and 2 WS patients(male).The proband(III-1)was diagnosed with MFS,showing congenital half ectopia lentis in both eye,high myopia in both eye,tall stature,scoliosis,wrist and thumb sign,chest asymmetry and hindfoot deformity.Other family members(II-2,II-5,III-2,III-4)showed characteristic phenotype of MFS in different extent.Meanwhile,there was a clinically suspicious MFS patient(II-4)who only showed tall stature,but no other manifestations of MFS were found.The patients(II-1 and III-3)were diagnosed with typical WS1 that manifested in congenital sensorineural deafness,heterochromic iris,dystopia canthorum and early white hair.A novel heterozygous mutation c.208T>C,p.Cys70 Arg in PAX3 from WS patients and another novel heterozygous mutation c.2740T>A,p.Cys914 Ser in FBN1 from MFS patients were identified and validated.Both mutations showed a co-segregation with the corresponding disease phenotypes.The conserved analysis of amino acid sites showed that these mutant amino acid residues were highly conserved.Conclusion: We identified two new heterozygous variants from a Chinese family with both MFS and WS.Our study can further expand the mutation spectrum of PAX3 and FBN1 in the WS and MFS,respectively,and will provide new gene targets for the treatment of these diseases,and is expected to provide data support for prenatal diagnosis and other gene-related analysis.