Congenital Hypothyroidism (Thyroid Dyshormonogenesis) via the TG Gene

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. It occurs in one of every 3,000-4,000 newborns and is twice as common in females as in males. Without early and adequate treatment, CH is characterized by growth failure, developmental delay, and permanent intellectual disability. Current newborn screening primarily detects the elevated thyroid stimulating hormone (TSH) level at birth in response to decreased or absent thyroid hormone production and can identify over 90% of CH cases. Most CH patients grow and develop normally after treatment with thyroxine (Park and Chatterjee. 2005; Rose et al. 2006).

CH is usually a sporadic disorder, but growing evidence confirms several genetic mechanisms together account for at least 5% of cases. The majority of CH cases (~80%) are due to developmental defects of the thyroid gland known as thyroid dysgenesis, including thyroid agenesis, hypoplasia, and ectopy. The remaining ~15% are caused by defects in one of the steps of thyroid hormone biosynthesis (thyroid dyshormonogenesis). Other less common causes are central hypothyroidism (impaired hypothalamic-pituitary-thyroid axis), thyroid hormone transporter defects, and thyroid hormone resistance (Péter and Muzsnai 2011; Nettore et al. 2013; Weber et al. 2013).

TG-related CH (thyroid dyshormonogenesis) is an autosomal recessive disorder (Grasberger and Refetoff 2011). The reported incidence of TG-related CH is about 1:67,000 in the Japanese population (Hishinuma et al. 2006). TG encodes thyroglobulin, a homodimer glycoprotein, exclusively synthesized in the thyroid gland. Thyroglobulin is the non-iodine component of thyroid hormone and also the storage pool of organified iodine (Grasberger and Refetoff 2011). At least 40 patients have been reported to harbor inactivating or loss of function TG mutations. Reported TG pathogenic variants include missense, nonsense, splicing variants, small deletions/insertions, and one gross deletion (Targovnik et al. 2011; Hishinuma et al. 2000; Narumi et al. 2011).

Congenital hypothyroidism (CH) is normally a sporadic disease, but in about 5% of cases a genetic cause has been demonstrated. Pathogenic variants in multiple genes from several molecular mechanisms are associated with CH (Péter and Muzsnai. 2011). At least 40 patients have been reported to harbor inactivating or loss of function TG mutations. In a population-based cohort of 102 patients with CH, pathogenic variants in TG were identified in five individuals (~5%) (Narumi et al. 2011). Gross deletion and duplication variants appear to be rare. A gross deletion affecting multiple exons of TG has been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TG gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).