ANALYSIS OF NOVEL THYROID PEROXIDASE GENE VARIANTS FROM THE GNOMAD DATABASE USING IN SILICO BIOINFORMATICS ALGORITHMS AND LITERATURE REVIEW

MOLINA, MARICEL F.; GOMES PIO, MAURICIO; SCHEPS, KAREN; ADROVER, EZEQUIELA; ABELLEYRO, MIGUEL M.; TARGOVNIK , HÉCTOR M.; RIVOLTA, CARINA M.

Mar del Plata

Congreso; LXVII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2022

Sociedad Argentina de Investigación Clínica

Thyroid peroxidase (TPO) is a thyroid-specific enzyme that plays a key role in thyroid hormones biosynthesis and is the major autoantigen in Hashimoto’s disease, the most common organ-specific autoimmune disease. TPO catalyzes both iodination and coupling of iodotyrosine residues within the thyroglobulin molecule. Variants in TPO gene cause congenital hypothyroidism (CH) by iodide organification defect and are commonly inherited in an autosomal recessive manner. In the present study, we report a detailed analysis and bioinformatic prediction of the TPO variants reported in the Genome Aggregation Database (gnomAD) v2.1.1. 456 variants from unrelated individuals were analized using prediction tools such us PROVEAN, SIFT, PolyPhen-2, Fsplice, among others. The proportion of missense cysteine, nonsense, frameshift, and splice acceptor/donor variants were analyzed in each ethnic group included in the gnomADv2.1.1 dataset. The results showed a clear predominance of frameshift variants in the East Asian (82%) and European (Finnish) (75%) population, whereas the splice site variants predominate in African/African Americans (99.46%), Other (96%), Latino/AdmixedAmerican (94%), South Asian (86%), European (Non-Finnish) (56%) and Ashkenazi Jewish (56%) populations with a significant p value <0.0001***. The analysis of the distribution of the variants revealed that most missense variants identified in the An peroxidase domain map in exon 8, followed by exons 11, 7 and 9. In total, 183 novelTPO variants were described (13 missense cysteine’s variants, 158 missense variants involving the An peroxidase domain and 12 splicing variants) which were not reported in the literature and that would have deleterious effects on prediction programs. The estimatedprevalence of heterozygous carriers of the potentially damaging variants was 1:77. In conclusion, we provide an updated and curated reference source of new TPO variants for application in clinical diagnosis and genetic counseling.