Analysis of genotype–phenotype relationships in 90 Chinese probands with Waardenburg syndrome

• DOI: 10.1007/s00439-021-02301-3
• Publication Date: 2021-06-17T16:07:26Z
• Authors: Guojian Wang; Xiaohong Li; Xue Gao; Yu Su; Mingyu Han; Bo Gao; Chang Guo; Dongyang Kang; Shasha Huang; Yongyi Yuan; Pu Dai
• Keywords: 0301 basic medicine; China; Microphthalmia-Associated Transcription Factor; 0303 health sciences; Genotype; Mosaicism; SOXE Transcription Factors; Pedigree; 03 medical and health sciences; Phenotype; Mutation; Humans; Waardenburg Syndrome; PAX3 Transcription Factor

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.