Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.

Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, characterized by typical facies, severe MR, epilepsy, and variable congenital malformations, including Hirschsprung disease (HSCR), genital anomalies, congenital heart disease (CHD), and agenesis of the corpus callosum (ACC). It is caused by de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22. ZFHX1B encodes Smad-interacting protein-1 (SMADIP1 or SIP1), a transcriptional corepressor involved in the transforming growth factor-beta signaling pathway. It is a highly evolutionarily conserved gene, widely expressed in embryological development. Over 100 mutations have been described in patients with clinically typical MWS, who almost always have whole gene deletions or truncating mutations (nonsense or frameshift) of ZFHX1B, suggesting that haploinsufficiency is the basis of MWS pathology. No obvious genotype-phenotype correlation could be identified so far, but atypical phenotypes have been reported with missense or splice mutations in the ZFHX1B gene. In this work we describe 40 novel mutations and we summarize the various mutational reports published since the identification of the causative gene.