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. 2019 Feb 27;2019:7143458.
doi: 10.1155/2019/7143458. eCollection 2019.

New Genotypes and Phenotypes in Patients With 3 Subtypes of Waardenburg Syndrome Identified by Diagnostic Next-Generation Sequencing

Free PMC article

New Genotypes and Phenotypes in Patients With 3 Subtypes of Waardenburg Syndrome Identified by Diagnostic Next-Generation Sequencing

Wu Li et al. Neural Plast. .
Free PMC article


Background: Waardenburg syndrome (WS) is one of the most common forms of syndromic deafness with heterogeneity of loci and alleles and variable expressivity of clinical features.

Methods: The technology of single-nucleotide variants (SNV) and copy number variation (CNV) detection was developed to investigate the genotype spectrum of WS in a Chinese population.

Results: Ninety WS patients and 24 additional family members were recruited for the study. Fourteen mutations had not been previously reported, including c.808C>G, c.117C>A, c.152T>G, c.803G>T, c.793-3T >G, and c.801delT on PAX3; c.642_650delAAG on MITF; c.122G>T and c.127C>T on SOX10; c.230C>G and c.365C>T on SNAI2; and c.481A>G, c.1018C>G, and c.1015C>T on EDNRB. Three CNVs were de novo and first reported in our study. Five EDNRB variants were associated with WS type 1 in the heterozygous state for the first time, with a detection rate of 22.2%. Freckles occur only in WS type 2. Yellow hair, amblyopia, congenital ptosis, narrow palpebral fissures, and pigmentation spots are rare and unique symptoms in WS patients from China.

Conclusions: EDNRB should be considered as another prevalent pathogenic gene in WS type 1. Our study expanded the genotype and phenotype spectrum of WS, and diagnostic next-generation sequencing is promising for WS.


Figure 1
Figure 1
Eighteen WS families with at least 2 DNA samples and clinical information collected in the study. Family ID and Subject ID were added to the individuals with DNA samples. A table with all data for family cases was shown in Table 1.
Figure 2
Figure 2
Multiple PCR target enrichment and next-generation Sequencing of WS-related genes.
Figure 3
Figure 3
The proportion of phenotypes detected in WS types 1, 2, and 4. Dystopia canthorum was the most frequent sign in WS type 1 (100%, 27/27), followed by sensorineural hearing loss (88.9%, 24/27), heterochromia iridis (81.5%, 22/27), hair hypopigmentation (14.8%, 4/27), constipation (1/27, 3.7%), and pigmentation spots (1/27, 3.7%). In WS type 2, sensorineural deafness (94.7%, 54/57) and heterochromia iridis (87.7%, 50/57) were still the most common clinical signs and symptoms, followed by freckles (31.6%, 18/57), hair hypopigmentation (24.6%, 14/57), hypopigmented skin lesions (5.3%, 3/57), and congenital ptosis (3.5%, 2/57). Amblyopia (1.8%, 1/57), congenital ptosis (1.8%, 1/57), and narrow palpebral fissures (1.8%, 1/57) are rare and unique symptoms in WS type 2 in the Chinese population.
Figure 4
Figure 4
The proportion of genotypes detected in WS types 1, 2, and 4 and the position in the protein domains of the new SNVs detected in our study.

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