Digenic Inheritance Mode in Congenital Hypothyroidism Due to Thyroid Dysgenesis: HYPOTYGEN Translational Cohort Study

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex.

Gain insight into the inheritance mode of CHTD.

Prospective multicenter nationwide translational study in France including 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes. Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation, and in vitro functional studies focusing on cell migration have been performed.

We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7% (14/182) and 3.9% (7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in 1 of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model.

This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up.