Abstract
Waardenburg syndrome (WS) characterized by sensorineural hearing loss and pigmentary abnormalities is genetically heterogeneous and phenotypically variable. This study investigated the molecular etiology and genotype-phenotype correlation of WS in 36 Chinese Han deaf probands and 16 additional family members that were clinically diagnosed with WS type I (WS1, n = 8) and type II (WS2, n = 42). Mutation screening of six WS-associated genes detected PAX3 mutations in 6 (86%) of the 7 WS1 probands. Among the 29 WS2 probands, 13 (45%) and 10 (34%) were identified with SOX10 and MITF mutations, respectively. Nineteen of the 26 detected mutations were novel. In WS2 probands whose parental DNA samples were available, de novo mutations were frequently seen for SOX10 mutations (7/8) but not for MITF mutations (0/5, P = 0.005). Excessive freckle, a common feature of WS2 in Chinese Hans, was frequent in WS2 probands with MITF mutations (7/10) but not in those with SOX10 mutations (0/13, P = 4.9 × 10−4). Our results showed that mutations in SOX10 and MITF are two major causes for deafness associated with WS2. These two subtypes of WS2 can be distinguished by the high de novo rate of the SOX10 mutations and the excessive freckle phenotype exclusively associated with the MITF mutations.
Highlights
Waardenburg Syndrome (WS) is relatively common among syndromic deafness, with an estimated prevalence of 1 in 42000 in the general population and 1–3% among the congenitally deaf[1]
We aimed to explore the molecular etiology and genotype-phenotype correlation in deaf patients associated with Waardenburg syndrome (WS)
While mutations in PAX3 were the major cause for WS1 (6/7), the molecular etiology of WS2 was heterogeneous and attributable to two major causative genes SOX10 (13/29) and MITF (10/29)
Summary
Waardenburg Syndrome (WS) is relatively common among syndromic deafness, with an estimated prevalence of 1 in 42000 in the general population and 1–3% among the congenitally deaf[1] It is mainly characterized by sensorineural deafness and various types of pigmentary abnormalities including heterochromic iridis, patchy de-pigmentation of the skin and premature graying of the hair. In WS2, heterozygous mutations in MITF and SOX10 are estimated to account for 15% of cases each, while heterozygous mutations in EDNRB and homozygous mutations in SNAI2 haven been identified in less than 5%5. WS1 and WS2 were two major subtypes of WS associated with hearing loss Unlike the former, WS2 is genetically heterogeneous and so far the genotype-phenotype correlation of the WS2 genes remains unclear. 50 Chinese Han deaf patients with WS type I and II were clinically characterized and genetically screened for mutations in PAX3, MITF, SOX10, SNAI, EDN3 and EDNRB. Our results showed that heterozygous mutations in MITF and SOX10, two major causes of WS2, have distinguishable de novo rates and clinical features
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