{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:17:26Z","timestamp":1790252246567,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Context<\/jats:title><jats:p>Congenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients, Design and Setting<\/jats:title><jats:p>Using the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed <jats:italic>in silico<\/jats:italic> for pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the <jats:italic>TG<\/jats:italic>, <jats:italic>DUOX2<\/jats:italic>, <jats:italic>TPO<\/jats:italic>, or <jats:italic>SLC5A5<\/jats:italic> genes in 10 infants and heterozygous variants in <jats:italic>DUOX2<\/jats:italic>, <jats:italic>TG<\/jats:italic>, <jats:italic>TPO<\/jats:italic>, and <jats:italic>TSHR<\/jats:italic> in 19 others. In seven cases, a heterozygous variant in the <jats:italic>TG<\/jats:italic> gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.657913","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T08:24:17Z","timestamp":1624523057000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With 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