OBJECTIVE: Pendred syndrome (PS) is characterized by the association of 
sensorineural hearing loss (SNHL) and a partial iodide organification defect at 
the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded 
transmembrane protein, called pendrin, has been found to be able to transport 
chloride and other anions.
DESIGN: The aim of the present study was to characterize a family with PS, which 
shows a strong intrafamilial phenotypic variability, including kidney atrophy in 
one member. The age of disease-onset was significantly different in all three 
affected siblings, ranging from 2 to 21 years for thyroid alterations and from 
1.5 to 11 years for SNHL.
METHODS: Clinical and genetic studies were carried out in affected siblings. The 
functional activity of the novel duplication found was studied by a fluorimetric 
method in a human renal cell line (HEK293 Phoenix) in which the protein was 
overexpressed.
RESULTS: All three siblings were found to be compound heterozygotes for the 
missense mutation (1226G>A, R409H) and for a novel 11 bp duplication 
(1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frame shift 
leading to the loss of the entire carboxy-terminus domain. Functional studies of 
this mutant demonstrated impaired transport of chloride and iodide when 
expressed in HEK 293 Phoenix cells, when compared with wild type pendrin.
CONCLUSIONS: A novel 11 bp duplication was found in a family with Pendred 
syndrome, showing a high intrafamilial phenotypic variability. An impaired 
transmembrane anionic transport of the mutated SLC26A4 protein was demonstrated 
in functional studies using a heterologous cell system.