A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease

Abstract

Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient.

Notch signaling regulates the differentiation of neural crest from human pluripotent stem cells

“…Our microarray data revealed several newly identified Notch targets, the expression of which is affected by DAPT treatment during neural crest differentiation -for instance APLNR, COL1A2, CDX1, IFITM1, LGALS1 and NDRG1 (supplementary material Table S2). Of note, our data suggest a significant role for JAG1 in neural crest development, supported by the fact that Jag1 knockout mice display semicircular canal hypoplasia (Humphreys et al, 2012;Tsai et al, 2001), a phenotypic feature found in neurocristopathies, such as Waardenburg (Sznajer et al, 2008) and CHARGE syndromes (Bajpai et al, 2010).…”

Review and update of mutations causing Waardenburg syndrome

“…In this regard, the so-called mild form of the Yemenite syndrome, due to a missense SOX10 mutation [Bondurand et al, 1999], can in fact be considered as a WS2 (possibly with a very mild neurological involvement, as nystagmus was reported). Other groups confirmed the occurrence of point mutations in WS2 or in PCW [Barnett et al, 2009;Iso et al, 2008;Sznajer et al, 2008]. Apart from the neurological signs of PCW/PCWH, other nonspecific features are associated with SOX10 mutations.…”

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

“…Temporal bone CT scans have been described for four patients known to be carrying mutations or heterozygous deletions in SOX10. Interestingly, three of these patients had severe morphological abnormalities of the inner ear: a WS4 patient carrying a SOX10 mutation had bilateral semicircular canal agenesis (Sznajer et al, 2008); a PCWH patient, carrying a large heterozygous deletion encompassing the entire SOX10 gene, had bilateral semicircular canal hypoplasia and vestibular malformation; and a WS2 patient, carrying a smaller heterozygous deletion within the SOX10 gene, had semicircular canal hypoplasia and dilatation, together with vestibular malformation and dilatation (Bondurand et al, 2007). These structural abnormalities correspond well to the defects that might be predicted from our analysis of the zebrafish model.…”