Abstract
ObjectiveThis study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss.MethodsA detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members.ResultsThe genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents.ConclusionWe revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.
Highlights
Waardenburg syndrome (WS) is a congenital developmental disorder, which is mainly characterized by congenital sensorineural hearing loss (SNHL) and abnormal pigmentation of the iris, hair, and skin (Read and Newton, 1997)
Six genes have been linked to this syndrome: paired box 3 (PAX3) (Baldwin et al, 1992; Tassabehji et al, 1992; Hoth et al, 1993), melanocyte inducing transcription factor (MITF) (Tassabehji et al, 1994), SRY-box transcription factor 10 (SOX10) (Pingault et al, 1998; Bondurand et al, 2007), endothelin 3 (EDN3) (Edery et al, 1996), endothelin receptor type B (EDNRB) (Puffenberger et al, 1994), and snail family transcriptional repressor 2 (SNAI2) (SánchezMartín et al, 2002)
Patients WS01II:1 and WS06-II:1 were primarily diagnosed with SNHL, while the other 12 patients were diagnosed with WS
Summary
Waardenburg syndrome (WS) is a congenital developmental disorder, which is mainly characterized by congenital sensorineural hearing loss (SNHL) and abnormal pigmentation of the iris, hair, and skin (manifests as heterochromia iridis and brilliant blue eyes, a white forelock, and premature graying, and hypopigmented skin) (Read and Newton, 1997). Not currently fully understood, all these genes are involved in a complex network in neural crest cells and other derivatives (Read and Newton, 1997; Bondurand et al, 2000; Pingault et al, 2010). The interaction of these genes during the formation and development of melanocytes could be the pathogenesis of WS and other related diseases (Read and Newton, 1997; Bondurand et al, 2000; Pingault et al, 2010)
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