OBJECTIVE: Pendred's syndrome is an association between congenital neurosensory 
deafness and goitre with abnormal discharge of iodide following perchlorate 
challenge, indicating a defect of iodide organification. Although Pendred's 
syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular 
basis of the association between the hearing loss and the thyroid organification 
defect remains unknown. We chose to investigate the role of the thyroid 
peroxidase (TPO) gene as the genetic defect in Pendred's syndrome.
DESIGN: A highly informative variable number tandem repeat (VNTR), located 1.5 
kb downstream of exon 10 of the TPO gene, was used to search for genetic linkage 
in multiple sibships affected by Pendred's syndrome.
PATIENTS: Seven kindreds were recruited from the UK, each with at least two 
affected members. We have also examined a large inbred Israeli family with two 
affected offspring and five unaffected children.
MEASUREMENTS: Individuals were assigned affected status based on the 
characteristic clinical features of Pendred's syndrome, namely the presence of 
congenital sensorineural hearing loss and the appearance in early life of a 
goitre. Additionally, at least one affected member from each sibship had a 
characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). 
PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes 
to each individual and the calculation of a two-point LOD score.
RESULTS: In six of the nine sibships analysed we found obligatory recombination 
between TPO and Pendred's syndrome. Non-complementation observed in affected 
parents with an affected offspring excluded TPO in an affected sibship with 
genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's 
syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's 
syndrome could not be excluded.
CONCLUSIONS: These data suggest that defects at the thyroid peroxidase locus on 
chromosome 2 are not the major cause of Pendred's syndrome.