Linkage analysis identifies the thyroglobulin gene region as a major locus for familial congenital hypothyroidism

Congenital hypothyroidism affects 1/3000–4000 new-borns and it has been estimated that 10–20% are familial cases with an autosomal recessive mode of inheritance. Previous studies of mostly individual cases have led to the identification of mutations in a number of genes, indicating that it is a genetically heterogeneous disease, but no major gene has been identified. In the present investigation, a population-based sample of 23 families with autosomal recessive congenital hypothyroidism, but no signs of goitre, were subject to linkage analysis. When markers located close to the thyroglobulin gene on chromosome 8q24 were used in a two-point analysis allowing for heterogeneity, a Zmax of 4.10 was obtained with the microsatellite marker D8S557, indicating heterogeneity with 43% of the families being linked. A multipoint analysis using the markers D8S557 and D8S1835 gave a Zmax of 3.51, assuming homogeneity. There was significant evidence of heterogeneity with 44.5% of the families being linked. The results indicate that a gene in 8q24 is a common cause of familial congenital hypothyroidism. Since thyroglobulin is essential for thyroid physiology, the gene encoding this protein is the obvious candidate for mutation analysis in the linked families.