Molecular and clinical characteristics of pediatric patients with primary congenital hypothyroidism: novel genetic variants and the genotype-phenotype association.

Background and aims: Primary congenital hypothyroidism (CH) was classified into thyroid dysgenesis(TD) and thyroid dyshormonogenesis(TDH) based on pathophysiology, and into permanent CH (PCH) and transient CH (TCH) based on outcomes after age two. Despite progress in identifying pathogenic genes and genetic variants, the genetic characteristics and genotype-phenotype correlations remained insufficiently explored. This study aimed to identify novel variants, assess their pathogenicity, and analyze the correlation between genotype and phenotype.

Subjects and methods: Clinical data from 97 pediatric patients with primary CH were collected (32 previously reported, 65 newly diagnosed). Next-generation sequencing was used to screen for variants, and statistical analysis was performed on the clinical data.

Results: Genetic etiologies were identified in 48% of patients, with 91% associated with TDH and 9% with TD. Six genes were involved: DUOX2 (68%), DUOXA2 (9%), TPO (9%), TG (6%), PAX8 (6%), and TSHR (2%). Seven novel variants were identified, including two pathogenic and five likely pathogenic. The TD-positive rate was significantly higher in the PCH group (43%) compared to the TCH group (0%). Genotype-phenotype analysis revealed that, at diagnosis, free thyroxine (FT4) levels were significantly lower in the genetic CH group compared to the carrier and wild-type groups. Additionally, the DUOX2 group had significantly higher free triiodothyronine (FT3) and FT4 levels at diagnosis compared to the non-DUOX2 group.

Conclusions: This study highlighted the significant role of genetic factors in primary CH, with DUOX2 being the most common pathogenic gene. Seven novel variants were identified, expanding the genetic spectrum. TDH might have been the main pathogenic mechanism, and TD was closely linked to PCH. Genetic CH was associated with lower FT4 levels, while DUOX2 variants correlated with milder biochemical phenotypes, further supporting genotype-phenotype correlations.