<i>DUOX2</i> / <i>DUOXA2</i> Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom

Abstract

<b><i>Background:</i></b> The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (<i>DUOX2</i>) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both <i>DUOX2</i> and its accessory protein <i>DUOXA2</i> may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of <i>DUOX2</i> and <i>DUOXA2</i> mutations in a borderline CH cohort. <b><i>Methods:</i></b> A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. <i>DUOX2</i> was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland <i>in situ</i>. <i>DUOXA2</i> was sequenced in <i>DUOX2</i> mutation-negative cases, and novel <i>DUOXA2</i> mutations were functionally characterized. <b><i>Results:</i></b> A total of 26 (50%) patients harbored likely pathogenic mutations in <i>DUOX2</i> (<i>n</i> = 20; 38%) or <i>DUOXA2</i> (<i>n</i> = 6; 12%), including novel gene variants (<i>DUOX2</i>, <i>n</i> = 3; <i>DUOXA2</i>, <i>n</i> = 7). Two recurrent <i>DUOX2</i> mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of <i>DUOX2</i> and <i>DUOXA2</i> mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (<i>M</i> = 9.3 pmol/L, range <3.9-15.8 pmol/L), <b><i>Conclusions:</i></b> Targeted <i>DUOX2</i> and <i>DUOXA2</i> sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring <i>DUOX2</i>/<i>DUOXA2</i> mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.