Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain

Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, i s a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an au tosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inhe rited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an a s-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and art hrogryposis. Each of the three patients was heterozygous for a SOX10 trunca ting mutation (Y313X in two patients and S351X in one patient). The extende d spectrum of the WS4 phenotype is relevant to the brain expression of SOX1 0 during human embryonic and fetal development. Indeed, the expression of S OX10 in human embryo was not restricted to neural-crest-derived cells but a lso involved fetal brain cells, most likely of glial origin. These data emp hasize the important role of SOX10 in early development of both neural-cres t-derived tissues, namely melanocytes, autonomic and enteric nervous system s, and glial cells of the central nervous system.