A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type II

Unraveling of Enigmatic Hearing-Impaired GJB2 Single Heterozygotes by Massive Parallel Sequencing

“…A subject with Waardenburg syndrome type II (WS2) in a large Chinese population had both MITF and GJB2 mutations in a compound heterozygous state. 17 The profound SNHL in the subject may have been caused by the digenic effect of GJB2 and MITF mutations, although the WS2 phenotype was caused by the MITF mutation. 17 In our studied family, SH107-225 with profound SNHL carried c.235delC in GJB2 and a de novo variant, p.R341C in MITF .…”

“…17 The profound SNHL in the subject may have been caused by the digenic effect of GJB2 and MITF mutations, although the WS2 phenotype was caused by the MITF mutation. 17 In our studied family, SH107-225 with profound SNHL carried c.235delC in GJB2 and a de novo variant, p.R341C in MITF . DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of p.R341C was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects.…”

Molecular Etiology of Hereditary Single-Side Deafness

“…WS1 is due to mutations in the PAX3 gene, whereas some WS2 cases are associated with mutations in the MITF gene. 32 The PAX3 gene is known to directly regulate the MITF gene expression. 17 , 33 While the mutation of MITF detected in WS2 appears to specifically affect survival, proliferation, and differentiation of melanocytes, PAX3 defects affect other neural crest cell derivatives, resulting in additional features of craniofacial malformations such as dystopia canthorum.…”

“… 34 WS2 also has been noted to display a broad spectrum of SNHL in terms of degree and pattern. 24 , 27 , 32 , 35 It is not clear whether these diverse clinical and auditory phenotypes of WS2 can be, to some extent, attributed to the genotypes. These variable clinical and auditory phenotypes could be mediated by genetic background or specific modifiers, as most patients with MITF mutations show variable penetrance of WS2-associated phenotypes, even within families segregating the same mutation.…”

Clue to a New Deafness Gene: A Large Chinese Nonsyndromic Hearing Loss Family Linked to DFNA4

“…Previous studies have revealed that one deafness locus can be linked to more than one gene (Bayazit and Yilmaz, 2006), and the question “one locus, how many genes?” was first raised about a decade ago (Van-Hauwe et al, 1999). So far, several loci, including DFNA2 and DFNA3, have been shown to be related to one or more genes, showing high genetic heterogeneity in hereditary hearing loss (Grifa et al, 1999; Goldstein and Lalwani, 2002; Yan et al, 2011). …”