SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis

Abstract

Pendred's syndrome (PDS) is an autosomal-recessive disorder characterized by sensorineural hearing loss and goiter. PDS is caused by mutations of the SLC26A4 gene encoding pendrin, a transmembrane exchanger of Cl(-), I(-) and HCO(3)(-), which is expressed in the thyroid and inner ear. SLC26A4 mutations can also be associated with non-syndromic deafness, DFNB4. The goal of our study was to define the identities and frequencies of SLC26A4 mutations in 563 large, consanguineous Pakistani families segregating severe-to-profound recessive deafness. Sequence analyses of SLC26A4 in 46 unreported families segregating deafness linked to DFNB4/PDS revealed 16 probable pathogenic variants, 8 of which are novel. The novel variants include three missense substitutions (p.R24L, p.G139V and p.V231M), two splice site mutations (c.304+2T>C and c.1341+3A>C), one frameshift (p.C565MfsX8) and two different genomic deletions affecting exons 1-2 and 11-18. Each of six pathogenic variants (p.V239D, p.Q446R, p.S90L, p.Y556C, p.R24L and p.K715N) was found in more than one family and haplotype analyses suggest that they are founder mutations. Combined with earlier reported data, SLC26A4 mutations were identified in 56 (7.2%; 95% CI: 5.6-9.2%) of 775 families. Therefore, SLC26A4 mutations are the most common known cause of genetic deafness in this population. As p.V239D (30%), p.S90L (18%) and p.Q446R (18%) account for approximately two-third of the mutant alleles of SLC26A4, hierarchical strategies for mutation detection would be feasible and cost-efficient genetic tests for DFNB4 deafness and PDS in Pakistanis.

The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations

“…In the cochlea, SLC26A4 is mainly expressed in regions of endolymph resorption; therefore, mutations in SLC26A4 may disturb endolymphatic fluid homeostasis (Borck et al, 2003). Anwar et al (2009) (Reardon et al, 1997;Park et al, 2003;Tsukamoto et al, 2003) (Table 2). …”

Evaluation of genotype–phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome

“…Today, the vast majority of patients are identified in infancy or childhood due to hearing impairment, andof the SLC26A4 gene. Approximately, 180 mutations have been reported (http://www.healthcare.uiowa.edu/labs/ pendredandbor/slcMutations.htm), which include missense, nonsense, splice site, and frameshift mutations, as well as partial gene deletions (4,5). Mutations in FOXI1 (6) and KCNJ10 (7) mutations have also been implicated in some cases of Pendred syndrome, although their role, if any, is likely to be minor (8,9).…”

Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss

“…We selected 107 individuals with SNHL and monoallelic mutations of SLC26A4 for MLPA analysis of the SLC26A4 gene to explore this further. A handful of multiexon SLC26A4 deletions have been described in the literature (Park et al, 2003;Hu et al, 2007;Pera et al, 2008a;Anwar et al, 2009;Siem et al, 2010) but it is unclear how many of the probands in these cohorts were tested for intragenic deletions and duplications. Recently, however, in a study of 109 Scandinavian probands with suspected PDS/DFNB4, 37 individuals with only one or zero mutations of SLC26A4 were systematically screened for copy number variants by MLPA (Rendtorff et al, 2013).…”

“…More than 260 mutations in the SLC26A4 gene have been identified to date (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC26A4), including deletions spanning multiple exons (Park et al, 2003;Hu et al, 2007;Pera et al, 2008a;Anwar et al, 2009;Siem et al, 2010).…”