Functional Noncoding Variants in a TTTG Microsatellite on Chromosome 15q26.1 Are a Common Genetic Etiology of Congenital Hypothyroidism with Thyroid Gland in situ.

Introduction: Variants affecting a microsatellite on the noncoding region of chromosome 15q26.1 are associated with familial non-autoimmune thyroid abnormalities characterized by mild congenital hypothyroidism (CH) with elevated thyroglobulin (Tg) levels. Some individuals who carry these variants may develop multinodular goiter if left untreated. Although these variants have been recognized as genetic etiologies of CH, nongoitrous, 3 (CHNG3), the associated severity of CH remains unclear.

Method: A cohort of 63 participants diagnosed with CH at Tohoku University underwent screening for genetic variants on 15q26.1. We then analyzed the clinical phenotypes of the variant-carrying participants.

Results: We identified five 15q26.1 variant carriers from four families among the cohort. Family histories of thyroid abnormalities were documented in three of these 5 cases. The variant carriers had mild CH phenotypes, with two discontinuing levothyroxine treatment and the others requiring relatively low doses (1.33-1.89 µg/kg/day) at their final visit. During levothyroxine treatment, serum Tg and thyroid-stimulating hormone (TSH) levels were within the reference ranges at the majority of the evaluation points. Three of the five participants continued treatment into adulthood, whereas the other two discontinued it and maintained serum TSH levels within the reference range. All five participants exhibited normal intellectual development and stature.

Conclusion: These findings provide further evidence supporting the role of 15q26.1 variants as a common genetic etiology of CH, with clinical phenotypes including transient CH. Early genetic evaluation may facilitate the identification of 15q26.1 variant carriers among patients who are diagnosed with CH.