Mutation spectra and genotype‑phenotype analysis of congenital hypothyroidism in a neonatal population

Congenital hypothyroidism (CH) is a common neonatal endocrine disorder that is characterized by irreversible neurodevelopmental and growth retardation due to insufficient biosynthesis of thyroid hormones at birth. Determining the causative genetic variants in infants is important for neonatal management. It was aimed to evaluate the variant frequencies and spectrum of CH in the neonatal population of Foshan, China. A total of 105 unrelated patients with CH and 138 controls from a neonatal screening program in Foshan, China were selected. A multiplex PCR amplification-based capture panel was performed which targeted the exon regions of 30 CH-related genes. Next-generation sequencing data were processed using an in-house bioinformatics system. A total of 91 variants distributed across 16 genes were identified in 74.29% (78/105) of the patients, of which 16 were novel variants and 75 were known variants. The most frequently mutated gene was DOUX2, followed by TG, TSHR and TPO. Specifically, DUOX2 variants p.Lys530Ter, p.Arg683Leu, p.Arg1110Gln, and IVS28 + 1G>T were highly recurrent in the cohort of the present study. Bi-allelic variants in DUOX2, TSHR and TPO were identified in 24.76% (26/105) of the patients. Monoallelic variants were identified in 28.57% (30/105) of the patients. Oligogenic variants were identified in 19.05% (20/105) of the patients. The most common variant combinations of oligogenic variants were DUOX2 and TG, and DUOX2 and SLC26A4. In addition, 2 patients harbored tri-allelic and tetra-allelic variants in DUOX2, respectively. In conclusion, DUOX2, TG, TSHR and TPO variants were the most common genetic defects in patients with CH in the neonatal population of Foshan. Specifically, biallelic DUOX2 variants were highly prevalent in the cohort. Further, the investigation provided a variant spectrum of CH-related genes and identified novel variants, which may allow for an improved understanding of the underlying genetic etiology of CH and provide evidence for further molecular epidemiological investigations that can guide preventive and therapeutic programs.