Congenital hypothyroidism (CH) occurs in approximately 1 in 3000 individuals. Rapid detection and treatment by neonatal screening and administration of T4, is essential to prevent severe mental retardation and impaired growth.
We report on two Welsh siblings, detected by neonatal screening, which had normal sized and placed glands but negative isotope uptake. Mutations resulting in CH are known to occur in 11 known genes, given the clinical presentation, we investigated the possibility of TSHR mutation.
Genomic DNA was obtained from both siblings and parents, the TSHR amplified using pairs of intronic and/or overlapping exonic primers and the PCR products sequenced automatically. Both siblings were homozygous for a previously described G to A transition producing a missense mutation, W546X, in the 4th membrane-spanning region of the TSHR. W546X results in a truncated protein, rendering it unresponsive to TSH.
Both parents were heterozygous and unrelated; furthermore the W546X has been described in 3 further families (including a second Welsh and 1 English family), suggesting it may be a relatively common mutation. We genotyped 368 euthyroid 'Welsh' individuals using single nucleotide primer extension, and found 366 homozygous wild type (G:G) and 2 heterozygous (G:A) for the mutation.
In conclusion, CH in the siblings is due to the missense mutation, W546X, in their TSHR gene. The W546X allele has a frequency of about 1 in 180 and may be a major contributor to CH in the Welsh population.