title: SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.
abstract: BACKGROUND
  Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4.
  
  
  METHODS
  A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein.
  
  
  CONCLUSIONS
  This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis.
authors.affiliation: Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Jalilian
authors.affiliation: Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Mohammad Amin
authors.initials: MA
authors.lastname: Tabatabaiefar
authors.affiliation: Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Alimadadi
authors.affiliation: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: nooridaloii@tums.ac.ir.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Noori-Daloii
mesh_terms: D000293:Adolescent; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006579:Heterozygote; D006801:Humans; D007492:Iran; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D055757:SOXE Transcription Factors / Q000235:genetics*; D014849:Waardenburg Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D055757:SOXE Transcription Factors
keywords: Chronic constipation; Hirschprung disease; Iran; SOX10; Waardenburg syndrome