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Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 ( DUOX2 ) occurring along with concurrent missense mutations in thyroid peroxidase ( TPO ), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in  DUOX2 ; one of them was also heterozygous for p.[R361L] in  TPO . The third patient was compound heterozygous for p.[L1160del]+[R1334W] in  DUOX2  and heterozygous for p.[P883S] in  TPO . This is the first report of a de novo L1160del mutation affecting the  DUOX2  gene and of the novel mutations Y1180X in  DUOX2  and R361L in  TPO . R1110Q and L1160del were found to reduce H 2 O 2  production (5%–9%, p&lt;0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H 2 O 2  production (–0.7%±0.6%, p&lt;0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H 2 O 2  production (24%±0.9%, p&lt;0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in  TPO , caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.

Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2