Combining whole-exome sequencing with clinical data for genotype–phenotype correlation in patients with congenital hypothyroidism that include the DUOX2 gene variation

Abstract Background: Clinical expression of DUOX2 gene variants is differential in patients with congenital hypothyroidism (CH). We investigated whether the molecular etiology of DUOX2 gene variants in CH patients can predict disease outcome, drug dosage, and follow-up period. Potential pathogenic variants were detected in 98 CH patients using whole-exome sequencing. Differences in diagnostic indicators and sustained Levothyroxine (L-T4)therapeutic dose between biallelic and monoallelic groups were compared. Results: The variant detection rate was 77.55%, and 149 variants were identified across 9 genes. Variants in the DUOX2 gene were of 50 types and showed the highest detection rate, with a frequency of 74.50% (111/149). Variants of interest were p.R1110Q (17.12%, 19/111) and p.K530* (16.22%, 18/111), where the former had a higher incidence of permanent hypothyroidism (PCH; 75%, 9/12). Patients with variants in the ferric oxidoreductase domain are more likely to develop PCH. Heel blood thyroid stimulating hormone (TSH) levels in the monoallelic group (176.50 [111.68, 272.50] mIU/L) were higher than those of the biallelic group (57.50 [15.30, 112.25] mIU/L; P = 0.001). The L-T4 doses of the monoallelic group at 1 and 3 years of age (36.83 ± 8.23 and 39.18 ± 15.71 µg/day, respectively) were significantly higher than those in the biallelic group (25.87 ± 9.05 and 25.38 ± 9.30 µg/day; P = 0.008 and P = 0.030, respectively). Conclusions: Patients with the p.R1110Q variant are more likely to develop PCH. Relatively high heel blood TSH levels in patients with normal-sized in situ glands harboring monoallelic DUOX2 variant evidenced increased doses and follow-up frequency during treatment.