Genetic Evaluation of Congenital Hypothyroidism with Gland Using Targeted Exome Sequencing

Objective: To analyze the genetic causes of congenital hypothyroidism through the targeted exome sequencing of pediatric patients with congenital hypothyroidism with thyroid gland METHOD: The study population included 20 patients diagnosed with congenital hypothyroidism with thyroid gland at the Pediatric Endocrinology Clinic of Pusan National University Hospital. Targeted exome sequencing was performed on eight causative genes, including thyroid stimulating hormone receptor (), mutation in which can cause hypothyroidism with a small or normal sized thyroid gland, and thyroglobulin (), thyroid peroxidase (), dual oxidase 2 (), dual oxidase maturation factor 2 (), iodotyrosine deiodinase (), solute carrier family 26 member 4 (SLC26A4), and solute carrier family 5 member 5 (), mutations in which are known to cause thyroid dyshormonogenesis.

Results: Permanent, subclinical, and transient hypothyroidism were diagnosed in 15 (75%), three (15%), and two (10%) patients, respectively. Genetic mutations were identified in 16 patients (80% positivity rate). Targeted exome sequencing of eight genes identified 24 variants in these patients: 11 variants in eight patients; six variants in five patients; five variants in three patients; and two variants in two patients. Of these 24 variants, 10 (41.6%) were novel. No variants were identified in , or . Two patients displayed triallelic (digenic) mutations (in and in one patient and and in the other). No variants were identified in three patients with permanent hypothyroidism and one patient with transient hypothyroidism. Genetic variations that could explain the congenital hypothyroidism phenotypes were identified in 12/15 cases (80%).

Conclusions: Targeted exome sequencing identified the genetic causes of congenital hypothyroidism with thyroid gland in 80% of the patients studied, with and mutations being the most common. As many of the identified variants were novel, additional studies on the genetic causes of congenital hypothyroidism are warranted.