Genotype and phenotype correlation in a cohort of Chinese congenital hypothyroidism patients with DUOX2 mutations

Background: This study aimed to explore the relationship between the phenotype and genotype of congenital hypothyroidism (CH) caused by dual oxidase 2 (DUOX2) mutation in Chinese children, and to investigate the genetic causes of permanent and transient hypothyroidism through next-generation genetic testing technology and long-term clinical follow-up data.

Methods: We recruited 61 patients with thyroid stimulating hormone (TSH) levels of >10 mIU/mL during newborn screening, clinical diagnosis of CH, and L-thyroxine (L-T4) oral treatment within 1 month of birth; they were followed up until the present. All CH infants and their parents were genotyped using whole-exome sequencing (WES); DUOX2 variants were detected in 20 infants, and the longitudinal prognosis, genotype, and phenotype correlations were analyzed.

Results: Biallelic DUOX2 mutations were detected in 20 participants. All of them were born full term. All patients were treated with L-T4 when diagnosed with CH; 9 of them stopped L-T4 eventually before 3 years old; and 2 were treated with a reduced dose of L-T4 (12.5 µg per day). The others were still treated with L-T4 at a dose of 37.5-87.5 µg per day. Of these 20 participants, 5 carried an R1110Q variant and 5 carried K530X variants. A total of 7 novel variants were discovered in our cohort. The variants carried in transient CH patients were located extracellularly and not near the functional domain.

Conclusions: Most CH patients with DUOX2 mutations were those with transient or subclinical CH. The R1110Q, R885L, and K530X were the most common variants in our Chinese cohort. The R1110Q and K530X variants may play a founder effect in the transient CH. The R885L variant may play a benign role in transient CH. Intracellular variants or those near the functional domain may cause permanent CH.