Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV

Viñuela, Antonio; Morín, Matías; Villamar, Manuela; Morera, Constantino; Lavilla, M. José; Cavallé, Laura; Moreno-Pelayo, Miguel A.; Moreno, Felipe; Castillo, Ignacio del

doi:10.1002/ajmg.a.33026

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…These results are consistent with animal studies in which heterozygous mutant Sox10 +/mut mice show a HL phenotype due to inner and outer hair cells and supporting cells (Deiters' cells) being absent in the cochlea . These results are consistent with the observation of abnormal morphology of the human inner ear according to the findings of MRI/CT scans in patients with SOX10 mutations .…”

Section: Discussionsupporting

confidence: 91%

Hearing loss in Waardenburg syndrome: a systematic review

et al. 2015

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Waardenburg syndrome (WS) is a rare genetic disorder characterized by hearing loss (HL) and pigment disturbances of hair, skin and iris. Classifications exist based on phenotype and genotype. The auditory phenotype is inconsistently reported among the different Waardenburg types and causal genes, urging the need for an up-to-date literature overview on this particular topic. We performed a systematic review in search for articles describing auditory features in WS patients along with the associated genotype. Prevalences of HL were calculated and correlated with the different types and genes of WS. Seventy-three articles were included, describing 417 individual patients. HL was found in 71.0% and was predominantly bilateral and sensorineural. Prevalence of HL among the different clinical types significantly differed (WS1: 52.3%, WS2: 91.6%, WS3: 57.1%, WS4: 83.5%). Mutations in SOX10 (96.5%), MITF (89.6%) and SNAI2 (100%) are more frequently associated with hearing impairment than other mutations. Of interest, the distinct disease-causing genes are able to better predict the auditory phenotype compared with different clinical types of WS. Consequently, it is important to confirm the clinical diagnosis of WS with molecular analysis in order to optimally inform patients about the risk of HL.

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Section: Discussionsupporting

confidence: 91%

Hearing loss in Waardenburg syndrome: a systematic review

et al. 2015

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“…A shortening of the cochlea due to a reduced sensory progenitor survival has recently been described in the Sox10 knock-out mouse [Breuskin et al, 2009]. These results are consistent with the observation that SOX10 mutations in human lead to morphological abnormalities of the inner ear at the MRI or CT-scan ( [Barnett et al, 2009;Inoue et al, 2004;Pingault et al, 2002;Sznajer et al, 2008;Vinuela et al, 2009] and manuscript in preparation).…”

Section: Biological Relevancesupporting

confidence: 86%

Review and update of mutations causing Waardenburg syndrome

et al. 2010

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Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling.

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“…Regarding Patient 2, we identified the de novo mutation c.915delG in exon 5. This deletion was previously reported, and generates a frameshift after codon 305, which would result in the addition of four aminoacid residues and a premature stop codon (p.His306Thrfs*5) [Viñuela et al, ]. The patient and both parents also carry the RET enhancer variant in heterozygosis.…”

Section: Mutational Screeningmentioning

confidence: 82%

“…In this sense, the c.915delG mutation (p.His306Thrfs*5), detected as a de novo event in Patient 2, would fit with the model of dominant‐negative activity resulting in neurological affectation since this patient, currently 16 years old, showed dysmielinization at MRI and is affected by severe psychomotor delay. Moreover, this deletion had been also reported to be associated to the PCWH phenotype [Viñuela et al, ], suggesting a genotype–phenotype correlation for this particular mutation.…”

Section: Discussionmentioning

confidence: 93%

Waardenburg syndrome type 4: Report of two new cases caused by SOX10 mutations in Spain

Fernández

Núñez-Ramos

Enguix-Riego

et al. 2013

American J of Med Genetics Pt A

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Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases.

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Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV

Cited by 11 publications

References 29 publications

Hearing loss in Waardenburg syndrome: a systematic review

Hearing loss in Waardenburg syndrome: a systematic review

Review and update of mutations causing Waardenburg syndrome

Waardenburg syndrome type 4: Report of two new cases caused by SOX10 mutations in Spain

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