SYSTEMATIC ANALYSIS OF THYROPEROXIDASE VARIATIONS IN PATIENTS WITH CONGENITAL HYPOTHYROIDISM.

MOLINA, MARICEL F.; ADROVER, EZEQUIELA; OLCESE, CECILIA; GÓMES PIO, MAURICIO ; SIFFO, SOFÍA; MIRAS, MIRTA; CHIESA, ANA; GONZÁLEZ-SARMIENTO, ROGELIO; TARGOVNIK, HÉCTOR M.; RIVOLTA, CARINA M.

Mar del Plata

Congreso; LXV Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica.; 2020

Sociedad Argentina de Investigación Clínica

The congenital hypothyroidism (CH) is the most common endocrine disease characterized by low levels of circulating thyroid hormones. The prevalence of CH is 1 in 2000-3000 live births. Variants in Thyroperoxidase (TPO) appear to be one of the causes of dyshormonogenesis with permanent CH. 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 intact catalytic site. In the present work, we present the analysis of 25 patients from 20 unrelated families with TPO variants identified in our laboratorory. We include the first case in which a variant in the TPO gene was identified worldwide, an argentinian boy presenting a homozygous duplication of a tetranucleotide GGCC in exon 8. All patients underwent clinical and biochemical evaluation. Sanger technique as well NGS technique using a custom panel targeting 8 genes associated with dishormonogenesis (TPO, IYD, SLC26A4, TG, DUOX2, DUOXA2, TSHR, SLC5A5) and bioinformatics analysis were performed. Our observation shows that variants in both TPO alleles were found in 16 families (2 as homozygote and 14 as heterozygote compound), whereas in 3 families only 1 variant was detected. In the remaing family, 1 TPO allele and 1 IYD allele showed variants. 20 different variants were identified of which 14 were novel (9 missense, 2 deletions, 1 nonsense, 1 duplication and 1 splicing). Additionally, we present an updated database from international bibliography and the Genome Aggregation Database (gnomAD). Our findings suggest monoallelic variants and oligogenic inheritance are also involved in the pathogenesis of CH. The identification and characterization of TPO variants is undoubtedly a valuable approach to study the TPO structure/function relations and for the elaboration of a clinical diagnosis and genetic counseling.