Abstract
Waardenburg syndrome (WS) is a phenotypically and genetically heterogeneous disorder characterised by hearing loss and pigmentary abnormalities. We clarified the clinical and genetic features in 90 Chinese WS probands. Disease-causing variants were detected in 55 probands, for a molecular diagnosis rate of 61%, including cases related to PAX3 (14.4%), MITF (24.4%), and SOX10 (22.2%). Altogether, 48 variants were identified, including 44 single-nucleotide variants and 4 copy number variants. By parental genotyping, de novo variants were observed in 60% of probands and 15.4% of the de novo variation was associated with mosaicism. Statistical analyses revealed that brown freckles on the skin were more frequently seen in probands with MITF variants; patchy depigmented skin, asymmetric hearing loss, and white forelocks occurred more often in cases with PAX3 variants; and congenital inner ear malformations were more common and cochlear hypoplasia III was exclusively observed in those with SOX10 variants. In addition, we found that ranges of W-index values overlapped between WS probands with different genetic variants, and the use of the W-index as a tool for assessing dystopia canthorum may be problematic in Chinese. Herein, we report the spectrum of a cohort of WS probands and elucidate the relationship between genotype and phenotype.
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Funding
This work was supported by grants from the Project of the Reproductive Health and Serious Birth Defect Prevention Research (National Key Research Project, 2016YFC1000704 2016YFC1000706), National Key Research Project (2017YFC1001804), National Natural Science Foundation of China (81730029, 81873704, and 81870731), Beijing Natural Science Foundation (7191011, 7192234), Project of the National Natural Science Foundation of China (81900953), Natural Science Foundation of Hainan Province (819MS110) and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar (2017-JQPY-001).
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Study protocols were performed with the approval of the Ethics Committee of the Chinese PLA General Hospital (approval number S2016-103-01).
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Wang, G., Li, X., Gao, X. et al. Analysis of genotype–phenotype relationships in 90 Chinese probands with Waardenburg syndrome. Hum Genet 141, 839–852 (2022). https://doi.org/10.1007/s00439-021-02301-3
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DOI: https://doi.org/10.1007/s00439-021-02301-3