Background: Lower cut-offs in TSH screening have doubled the incidence of congenital hypothyroidism (CH), particularly cases with an eutopically-located Gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes, or the thyrotropin-stimulating hormone receptor (TSHR) may underlie such cases, these genes have not previously been screened comprehensively in a GIS CH cohort.
Study design: We evaluated the relative contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD and TSHR) in fifty-one CH cases with GIS from 35, ethnically diverse families, using next generation sequencing. Patient genotypes were correlated with biochemical phenotype and pathogenicity of novel mutations analysed in silico.
Results: Twenty-nine cases harboured likely, disease-causing, mutations. Twenty cases with single gene defects, most commonly involving TG (12 cases), TPO (five cases), DUOX2 (two cases) and TSHR (one case), were documented. Novel variants were identified in TG (13), TPO (6), and DUOX2 (3). Nine cases harboured pathogenic variants in two different genes: TG and TPO (1 case); SLC26A4 and TPO (two cases) and DUOX2 and TG (six cases). However, family studies in such digenic cases, showed no clear correlation between genotype and phenotype. Genetic aetiology was not ascertained in 22 patients, generally with milder biochemical CH and including some familial cases.
Conclusions: The aetiology of CH with GIS is complex, with only 57% being due to mutations in TSHR or known dyshormonogenesis-associated genes. Combinations of defects in two different genes are common, especially in consanguineous families. Severe CH is most commonly mediated by biallelic TG or TPO mutations. A high proportion (~43%) of unsolved cases suggests contribution of hitherto unknown genes or environmental factors to GIS CH.