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Neurological Phenotype in Waardenburg Syndrome Type 4 Correlates with Novel SOX10 Truncating Mutations and Expression in Developing Brain

{ "0" : "Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital Necker-Enfants Malades, Paris" , "1" : "Centre de Génétique, Hôpital d'Enfants, Dijon, France" , "2" : "Kinderkrankenhaus, Kliniken der Stadt Köln" , "3" : "Institut für Genetik, Universität zu Köln, Cologne, Germany" , "4" : "Unité de Génétique Médicale et Foetopathologie, Hôpital Arnaud de Villeneuve, Montpellier, France" , "5" : "Génétique Moléculaire et Physiopathologie, Hôpital Henri Mondor, Créteil, France" , "7" : "Ataxia" , "8" : "Dysautonomia" , "9" : "Hirschsprung disease" , "10" : "Neuroscristopathy" , "11" : "Waardenburg syndrome"}
The American Journal of Human Genetics (Impact Factor: 10.99). 06/2000; 66(5):1496-1503. DOI: 10.1086/302895
Source: PubMed

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

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    ABSTRACT: Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype–phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype–phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. © 2014 Wiley Periodicals, Inc.
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May 19, 2014