Abstract
Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare genetic disorder with a prevalence of <1/1,000,000 and characterized by the association of congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. There are three types of WS4 (WS4A–C) caused by mutations in endothelin receptor type B, endothelin 3, and SRY-box 10 (SOX10), respectively. This study investigated a genetic mutation in a Chinese family with one WS4 patient in order to improve genetic counselling. Genomic DNA was extracted, and mutation analysis of the three WS4 related genes was performed using Sanger sequencing. We detected a de novo heterozygous deletion mutation [c.1333delT (p.Ser445Glnfs*57)] in SOX10 in the patient; however, this mutation was absent in the unaffected parents and 40 ethnicity matched healthy controls. Subsequent phylogenetic analysis and three-dimensional modelling of the SOX10 protein confirmed that the c.1333delT heterozygous mutation was pathogenic, indicating that this mutation might constitute a candidate disease-causing mutation.
Highlights
Waardenburg syndrome type 4 (WS4) is known as Waardenburg-Shah syndrome (OMIM 277580) and is characterized by hearing loss, depigmentation, and aganglionic megacolon (Hirschsprung disease)
A 1-year-old male patient was referred to our hospital with the chief complaint of Hirschsprung disease accompanied by heterochromia iridis and congenital hearing loss
A heterozygous deletion mutation (c.1333delT) in SRY-box 10 (SOX10) was identified in the patient, resulting in replacement of the 445th Ser with Gln and a shift in the reading frame to produce a longer protein consisting of 501 amino acids (p.Ser445Glnfs*57) as compared with the wild-type SOX10 protein (467 amino acids; Fig. 2, Table 2)
Summary
WS4 is known as Waardenburg-Shah syndrome (OMIM 277580) and is characterized by hearing loss, depigmentation, and aganglionic megacolon (Hirschsprung disease). WS4 includes three subtypes [WS4A–C (OMIM 277580, 613265, and 613266)] caused by mutations in EDNRB, EDN3, and SOX10, respectively[7,8,9]. Mutations in EDNRB and EDN3 are inherited in the autosomal recessive (AR) or autosomal dominant (AD) form, whereas the SOX10 mutation is inherited as AD10–13 and found in ~50% of WS4 patients[1,6], with >30 WS4-related mutations reported in the Human Gene Mutation Database. SOX10 is a critical transcription factor, targeting MITF, tyrosinase, myelin protein zero, gap junction protein beta 1, ret proto-oncogene, and EDNRB during neural-crest-derived cell migration and differentiation. SOX10 modulates the expression of its target genes and the migration of pluripotent neural crest cells from the neural tube during embryogenesis[14,15]. Our findings indicated that this mutation might be a candidate disease-causing mutation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
