Can simultaneous mutations in TSHR and DUOX2 cause congenital hypothyroidism?

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The etiology of congenital hypothyroidism (CH) is largely unknown. A minor subset of CH patients has single gene mutation. However, it has not been studied whether simultaneous mutations in two or more genes can cause CH. In the present study, we enrolled and sequenced 401 CH patients, and found 4 patients that had heterozygous mutations in the TSH receptor gene (TSHR) and the dual oxidase 2 gene (DUOX2) simultaneously ("double heterozygotes"). Based on the frequencies of heterozygotes of TSHR (1/172) and DUOX2 (1/67), such double heterozygotes are expected to be observed in 1/11,524 in the general population. Thus, considering the frequency of CH (1/3,000) and the frequency of double heterozygotes among CH patients (4/401), most double heterozygotes are not affected by CH. Nonetheless, extremely high rate of double heterozygotes among CH patients, as compared with among the general population, indicates that simultaneous mutations in TSHR and DUOX2 acts as a strong risk factor for CH.