Can simultaneous mutations in TSHR and DUOX2 cause congenital hypothyroidism?

先天性甲状腺功能减退症（CH）的病因在很大程度上是未知的。CH患者的一小部分具有单基因突变。然而，它还没有被研究是否同时在两个或两个以上的基因突变会导致CH。在本研究中，我们招募和测序401 CH患者，并发现4例患者的TSH受体基因（TSHR）和双氧化酶2基因（DUOX 2）同时杂合突变（“双杂合子”）。根据TSHR（1/172）和DUOX 2（1/67）杂合子的频率，预计在一般人群中观察到1/11，524的双杂合子。因此，考虑到CH的频率（1/3，000）和CH患者中双杂合子的频率（4/401），大多数双杂合子不受CH的影响。然而，与普通人群相比，CH患者中极高的双杂合子率表明TSHR和DUOX 2的同时突变是CH的一个强风险因素。

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.