IYD – Familial Thyroid Dyshormonogenesis

Iodotyrosine deiodinase 1 (IYD) is essential for iodide recycling in thyroid hormone synthesis and is implicated in familial thyroid dyshormonogenesis. Biallelic loss-of-function variants cause an autosomal recessive form of congenital dyshormonogenesis, characterized by elevated urinary iodotyrosines. In a consanguineous family, two siblings homozygous for c.658G>A (p.Ala220Thr) exhibited elevated monoiodo- and diiodotyrosine levels; the variant co-segregated with disease status (PMID:18765512). Broad screening of 104 dyshormonogenesis cases did not identify additional IYD variants, highlighting the rarity of IYD-associated disease (PMID:23236987; PMID:30154845). The limited number of unrelated probands and absence of recurrence restricts the genetic evidence.

Functional assays in HEK293 cells demonstrated that p.Ala220Thr abolishes dehalogenase activity, establishing a loss-of-function mechanism concordant with the recessive clinical phenotype (PMID:18765512). Heterozygous carriers may show incomplete penetrance of hypothyroidism, but no conflicting evidence has been reported. Further population studies and in vivo modeling are needed to reach a definitive association. Key Take-home: Genetic testing of IYD and in vitro enzyme assays offer clinical utility for diagnosing rare autosomal recessive familial thyroid dyshormonogenesis.

References

• The Journal of clinical endocrinology and metabolism • 2008 • Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism. PMID:18765512
• Clinical endocrinology • 2013 • Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. PMID:23236987
• International journal of endocrinology • 2018 • Mutational Spectrum Analysis of Seven Genes Associated with Thyroid Dyshormonogenesis. PMID:30154845

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