CONICET | Buscador de Institutos y Recursos Humanos

The congenital hypothyroidism (CH) is the most common endocrine disease characterized by lowlevels of circulating thyroid hormones. The prevalence of CH is 1 in 2000-3000 live births. Variantsin Thyroperoxidase (TPO) appear to be one of the causes of dyshormonogenesis with permanentCH. TPO is a membrane-bound glycoprotein. The TPO gene is located in chromosome 2 [2p25],comprises 17 exons, covers approximately 150 kb of genomic DNA and encodes 933 amino acids.The TPO enzyme activity depends on both proper folding and membrane insertion, and an intactcatalytic site. In the present work, we present the analysis of 25 patients from 20 unrelated familieswith TPO variants identified in our laboratorory. We include the first case in which a variant in theTPO gene was identified worldwide, an argentinian boy presenting a homozygous duplication of atetranucleotide GGCC in exon 8. All patients underwent clinical and biochemical evaluation. Sangertechnique as well NGS technique using a custom panel targeting 8 genes associated withdishormonogenesis (TPO, IYD, SLC26A4, TG, DUOX2, DUOXA2, TSHR, SLC5A5) and bioinformaticsanalysis were performed. Our observation shows that variants in both TPO alleles were found in 16families (2 as homozygote and 14 as heterozygote compound), whereas in 3 families only 1 variantwas detected. In the remaing family, 1 TPO allele and 1 IYD allele showed variants. 20 differentvariants were identified of which 14 were novel (9 missense, 2 deletions, 1 nonsense, 1 duplicationand 1 splicing). Additionally, we present an updated database from international bibliography andthe Genome Aggregation Database (gnomAD). Our findings suggest monoallelic variants andoligogenic inheritance are also involved in the pathogenesis of CH. The identification andcharacterization of TPO variants is undoubtedly a valuable approach to study the TPOstructure/function relations and for the elaboration of a clinical diagnosis and genetic counseling.