Waardenburg syndrome

Waardenburg syndrome is a genetic complex of symptoms first described in the 1950s and that is evident at birth.

For many years each genetic syndrome was considered a complex of several defects or symptoms. It was presumed that all patients with the same syndrome would have defects in the same gene (or chromosome). The implementation of molecular tests revealed that many “classical” syndromes are genetically heretogeneous, i.e. changes in different genes or chromosomes may cause an identical (or almost identical) clinical picture. Waardenburg syndrome may be an example of such a heterogeneity.

Waardenburg syndrome was delineated in the early 1950s by the Dutch ophthalmologist Petrus Waardenburg who noted that persons with heterochromic irides (different colored eyes) frequently also have hearing impairment. Defects of the eyes and hearing problems are the main manifestations of this syndrome. It was shown that patients with this condition also may have a lateral displacement of the inner canthi (inner corners) of the eyes. Currently this complex (heterochromia, dystopia canthorum and deafness) is called Waardenburg syndrome type I (WS-I)1. A similar phenotype without dystopia canthorum is called Waardenburg syndrome type II (WS-II). There are also very rare types III and IV (these patients may have additionally limb defects (for type III) or Hirschsprung disease (for type IV), but more than 95% of all patients belong to types I and II. The syndrome is inherited as an autosomal dominant trait with exceptionally high clinical variations even within a family having the same genetic defect.

The vast majority of patients with WS-I have defects of the PAX3 gene2. During embryogenesis this gene encodes a transcription factor in neural crest cells of the spinal ganglia, the craniofacial mesoectoderm, and the limb mesenchyme. It plays an important role in the migration and differentiation of melanocytes originated from the embryonic neural crest2. The PAX3 gene is located at the long arm of chromosome 2 (2q36.1 segment) and patients having deletions of 2q36.1 involving the PAX3 gene reveal the classical phenotype of WS-I syndrome. There are ~40 known patients with WS-I caused by deletions involving 2q36.1. Some deletions affect only several exons of the gene, but in most reported cases deletions involve the whole gene and sometimes several neighboring genes. If no other genes are involved, the clinical manifestations of the persons with deletions are not different from the clinical picture in persons having point mutations in the PAX3 gene.

WS-II is caused by a defective function of the SOX10 gene. This gene is a transcription factor for the development of a neural crest. SOX10 is crucial for the survival and maintenance of migrating neural crest progenitors and influences differentiation at later stages3. SOX10 is located at the long arm of chromosome 22 (segment 22q13.1). Most persons with WS-II have point mutations in this gene. However, a significant number of patients have deletions involving SOX10. At least 30 patients with WS-II caused by deletions have been reported so far. Deletions may affect the whole gene or only several exons. Moreover, there are patients where the SOX10 gene itself is intact, but there is a deletion of regulatory elements located outside the gene4. It should be noted that the variability of clinical manifestations may be so wide that some persons having SOX10 (as well as PAX3) deletions may reveal no clinical signs of the disease.

Deletions of the distal segment of 22q are associated with Phelan-McDermid syndrome (PMDS). Most patients with PMDS have relatively small deletions affecting only the 22q13.3 area. However, some may have much larger deletions involving 22q13.1 and these patients may also have manifestations of WS-II syndrome.

WS-III is caused mainly by defects in the MITF gene, located at the short arm of chromosome 3 (3p13 segment). However this form is rare, and there are only several publications5 about patients with this form of Waardenburg syndrome caused by deletions of this gene.

All forms of the syndrome are inherited as autosomal dominant conditions. As a rule, these patients do not have other abnormalities, and their intellectual development is normal.


1Bocángel MAP, Melo US, Alves LU et al. (2018). Waardenburg syndrome: novel mutations in a large Brazilian sample. Eur J Med Genet, 61(6), 348-354.

2Yang S-Z, Hou L, Qi X et al. (2023). A gross deletion of the PAX3 gene in a large Chinese family with Waardenburg syndrome type I. World J Pediatr, 19 (12): 1203-1207.

3Bondurand N, Destot-Le Moal F, Stanchina L, et al. (2007). Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am J Hum Genet, 81(6): 1169-1185.

4Huang Y, Geng J, Long Y et al. (2024). Five novel cis-regulatory deletions of SOX10 cause Waardenburg syndrome type II. Front. Audiology and Otology 2:1400991.

5Wang G, Li X, Gao X et al. (2022). Analysis of genotype-phenotype relationships in 90 Chinese probands with Waardenburg syndrome. Hum Genet 141 (3-4): 839-852.

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