Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder with a genetic origin. The purpose of the present study was to analyze the mutation spectrum of CH patients in China. A targeted next-generation sequencing panel covering all exons of 29 CH-related causative genes was used in 43 Han Chinese patients with CH [11 dysgenesis and 32 glandsin situ(GIS)]. The functional impact and pathogenicity of detected variants were analyzed using a comprehensive bioinformatics approach and co-segregation studies. A total of 47 rare non-polymorphic variants in 9 target genes associated with thyroid hormone synthesis (DUOX2, DUOXA2, TPO, TG, SLC26A4andSLC5A5), thyroid stimulating hormone resistance (TSHR) and central hypothyroidism (PROP1andTRHR) were identified in 31 patients (31/43, 72%). Of these variants, 8 were novel, including 3 inDUOX2, 2 inTPO, 3 inTSHRand 1 inSLC5A5. Variants were mostly affected byDUOX2, TG, TPOandTSHR. Approximately 44% of the patients (19/43) carriedDUOX2variants. The mutation detection rates in patients with GIS were higher compared with patients with dysgenesis [25/32 (78%) vs. 6/11 (54%)]. Oligogenic mutations were detected in 25.6% of the total cases and 35% of the mutated cases. Genetic basis was ascertained in 13 patients, reaching a diagnosis detection rate of 30%. In conclusion, genetic defects in dyshormonogenesis, mainly inDUOX2, were the main genetic cause of CH in the Chinese population. Oligogenicity is highly involved in CH pathogenesis and may thus be an important factor in common phenotypic variability observed in patients with CH.