Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4

Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.     

Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome

Waardenburg syndrome (WS) is a rare disorder characterized by distinctive facial features, pigment disturbances, and sensorineural deafness. There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups, but the data from Chinese patients with WS remains poor. Herein we report 18 patients from 15 Chinese WS families, in which five cases were diagnosed as WS1 and the remaining as WS2. Clinical evaluation revealed intense phenotypic variability in Chinese WS patients. Heterochromia iridis and sensorineural hearing loss were the most frequent features (100% and 88.9%, respectively) of the two subtypes. Many brown freckles on normal skin could be a special subtype of cutaneous pigment disturbances in Chinese WS patients. PAX3, MITF, SNAI2, and SOX10 genes mutations were screened for in all the patients. A total of nine mutations in 11 families were identified and seven of them were novel. The SOX10 mutations in WS2 were first discovered in the Chinese population, with an estimated frequency similar to that of MITF mutations, implying SOX10 is an important pathogenic gene in Chinese WS2 cases and should be considered for first-step analysis in WS2, as well as MITF.     

Screening of MITF and SOX10 Regulatory Regions in Waardenburg Syndrome Type 2

Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.