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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 HCO3−, 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.Journal of Human Genetics (2009) 54, 266–270; doi:10.1038/jhg.2009.21; published online 13 March 2009 [ABSTRACT FROM AUTHOR]

Mutations of PCDH15, encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or nonsyndromic deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating nonsyndromic deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F, which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15, mutations in the introns or regulatory elements of PCDH15, or an additional locus for type I USH at chromosome 10q21.1. [ABSTRACT FROM AUTHOR]

We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72, on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS, ZNRF4 and CAPS. We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68, the only other known deafness locus with statistically significant support for linkage to chromosome 19p. [ABSTRACT FROM AUTHOR]