ALB, SECISBP2, SLC16A2, THRA, THRB AND TSHR GENE ANALYSIS
Thyroid hormone resistance, also known as Impaired sensitivity to thyroid hormone, is characterized by a reduced responsiveness of target tissues to thyroid hormone and is primarily caused by germline pathogenic variants in the thyroid hormone receptor beta (THRB) gene. The mutant receptor has lower binding affinity for thyroid hormone and, as a consequence, serum thyroid-stimulating hormone (TSH) levels remain nonsuppressed despite elevated thyroid hormones (Dumitrescu and Refetoff 2013 Biochim Biophys Acta. 1830:3987–4003). Patients with pathogenic variants in THRB also present with goitre and the absence of symptoms of thyrotoxicosis. Clinical phenotypes can be highly variable depending on the degree of tissue responsiveness to elevated thyroid hormone levels in a given individual; the same variant can result in different phenotypes in different patients, even within the same family. In general, heterozygous pathogenic variants in THRB are sufficient to cause disease. Patients homozygous for variants in THRB have a more severe phenotype than patients with heterozygous variants (Ortiga-Carvalho et al. 2014 Nat. Rev. Endocrinol. 10: 582–591).
Pathogenic variants in THRA lead to a clinically distinct phenotype from the phenotype caused by pathogenic variants in the THRB gene. Patients with THRA variants have circulating TSH levels within the normal range, slightly lowered levels of free T4 and slightly elevated levels of total T3 but display hypothyroidism, delayed growth and constipation (Ortiga-Carvalho et al. 2014 Nat. Rev. Endocrinol. 10: 582–591). THRA is analysed as part of our Congenital Hypothyroidism panel (https://www.exeterlaboratory.com/genetics/congenital-hypothyroidism/).