Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics

Abstract

ObjectivesTill date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures.DesignProspective analysis.Patients19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype–phenotype analyses.SettingAll analyses were performed in a large German laboratory specialised in genetic diagnostics.Results15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation.ConclusionsOn the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype–phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.

Pigment Genodermatoses Affecting Melanocyte Development and Migration from the Neural Crest: Piebaldism, Waardenburg Syndrome and Cross- McKusick-Breen Syndrome

“…The PAX gene family also encodes a DNA-binding transcription factor expressed in neural crest cells. It plays an important role for the migration and differentiation of melanocytes, which originate from the embryonic neural crest [19]. PAX3 protein is also necessary for the formation of nerve and muscle tissue and certain craniofacial bones.…”

“…Type III or Klein-Waardenburg syndrome is a severe form of type I presenting with skeletal abnormalities. Type IV or Shah-Waardenburg syndrome is characterized by the association of WS and Hirschsprung disease [18,19].…”

Estudo genético e molecular da síndrome de Waardenburg

“…Em um recente estudo molecular da síndrome de Waardenburg com uma casuística de 119 probandos [Wildhardt et al, 2013] foram utilizadas as técnicas de sequenciamento convencional dos genes PAX3 e MITF, e a técnica de MLPA dos genes MITF, PAX3 e SOX10. Foram detectadas 19 mutações, 14 no gene PAX3 e 5 no MITF.…”

“…• Na Alemanha, onde onze novas mutações foram descritas neste gene em um estudo envolvendo 119 pacientes com a SW [Wildhardt et al, 2013], e;…”

“…Deleções parciais ou totais do gene PAX3 também foram descritas , Kozawa et al, 2008, Milunsky et al, 2007, Wang et al, 2010a, Wildhardt et al, 2013. No banco de dados do DECIPHER (https://decipher.sanger.ac.uk) foram descritas 3 deleções totais do gene, associadas com algumas características da síndrome como hipertelorismo e heterocromia.…”