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Waardenburg syndrome type IIE in a Japanese patient caused by a novel non‐frame‐shift duplication mutation in the SOX10 gene

Dear Editor, SOX10 plays an essential role in the development of cells in the neural crest lineage, including melanocytes and enteric ganglia neurons. Mutations in SOX10 have been found in patients with Waardenburg syndrome (WS) type 2 (WS2E, Online Mendelian Inheritance in Man [OMIM] no. 611584), WS4 (WS4C, OMIM no. 613266; this subtype is associated with Hirchsprung disease [HD]), peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS and HD (PCWH, OMIM no. 609136), and Kallman syndrome. However, the reason for phenotypic heterogeneity in patients with nontruncating mutations in SOX10 remains unknown; the rs2435357 polymorphism in RET, which is statistically associated with the development of HD, has been investigated in several WS patients searching for the genetic modifier. We also recently reported a patient with WS2 (without HD) harboring a heterozygous p.N131D mutation in SOX10 who had no risk allele in rs2435357. Here, we additionally report a familial case of WS2E with a novel non-truncating mutation in SOX10. The patient was 8-month-old girl presenting bilateral blue irides and sensorineural hearing impairment. Piebald leukoderma, white forelock, dystopia canthorum, limb anomaly, motor impairment or HD were absent, suggesting that she was clinically divided into WS2 (Fig. 1a). Her symptoms were similar to her father (Fig. 1b) and her paternal grandmother, indicating autosomal dominant inheritance. The patient and her parents provided written informed consent for participation in this study, which was conducted according to a protocol approved by the ethics committee of the Yamagata University Faculty of Medicine. Mutational screening for MITF and SOX10 showed a novel heterozygous duplication mutation, c.381_386dupGCACCT (p.L129_H130dup), in SOX10 (Fig. 1c). Genotyping for rs2435357 revealed that both the patient and her father were homozygous for the C allele (risk allele for the HD is T allele). While the major gene playing a role for HD susceptibility is RET, SOX10 has been demonstrated to directly activate RET transcription in synergy with PAX3 at the RET enhancer region. In addition, the T allele (frequency in Asia, 0.45) in rs2435357 alters a functional SOX10 binding site and results in a lower level of expression of RET in vitro. So, it is reasonable to genotype rs2435357 (a common RET intronic polymorphism located in an enhancer) as a strong candidate genetic modifier for the WS patients with SOX10 mutation. However, the impact of the T allele to the development of HD in patients with SOX10 mutations has not been proved yet, awaiting further study. The phenotypes of our patient and our previously reported patient were very similar; both of them only revealed bilateral blue irides and sensorineural hearing impairment but no other specific manifestations of WS. One may speculate that this can be partially explained by the close position of amino acid alteration (p.L129_H130dup and p.N131D). One may also speculate that the absence of the risk allele in rs2435357, which was common among them, may affect their mild phenotypes. Our sequential reports accentuated the importance of