Congenital Hypothyroidism and Thyroid Hormone Resistance Panel

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 10% 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 (Peter and Muzsnai 2011; Nettore et al. 2013; Weber et al. 2013; Grasberger and Refetoff 2011). Thyroid hormone resistance (THR) is a rare genetic disorder caused by reduced tissue responsiveness to thyroid hormone. The estimated prevalence is about 1:40,000 births. The characteristic biochemical findings in patients with THR are elevated serum free thyroid hormone levels accompanied by nonsuppressed thyroid stimulating hormone production (Dumitrescu et al. 2013). The clinical presentation is highly variable and has a mixture of hypothyroidism and hyperthyroidism because of variable peripheral resistance among individuals as well as among different tissues within a single patient. Goiter is found in 66-95% of reported cases. Symptoms related to hypothyroidism include learning disabilities, delayed growth and bone development. Hyperactivity and tachycardia are associated with high thyroid hormone levels. In the mild form of THR, isolated biochemical abnormalities may be the only findings (Dumitrescu et al. 2013; Ferrara et al. 2012; Amor et al. 2014). A defect in the thyroid hormone receptor beta gene (THRB) accounts for almost 85% of THR cases. Heterozygous pathogenic variants in the thyroid hormone receptor alpha gene (THRA) lead to a rare form of THR with congenital hypothyroidism as the predominant clinical presentation (van Mullem et al. 2014).

This NextGen test analyzes 26 genes leading to monogenic forms of congenital hypothyroidism and/or thyroid hormone resistance. Thyroid disorders listed below are inherited as autosomal dominant (PAX8, NKX2-1, NKX2-5, GNAS, and THRA) or recessive (SLC26A4/PDS, SLC5A5/NIS, TPO, TG, IYD/DEHAL1, DUOXA2, TSHB, SECISBP2, GLIS3, FOXE1, TRHR, PROP1 and UBR1), or X-linked (IGSF1 and SLC16A2) conditions. TSHR, POU1F1, HESX1, DUOX2, or THRB -associated diseases can present with either dominant or recessive patterns of inheritance (Péter and Muzsnai 2011; Grasberger and Refetoff 2011, Dumitrescu et al. 2013; Nettore et al. 2013). Primary thyrotropin-releasing hormone deficiency is expected to be caused by loss of function TRH variants. However, no pathogenic variants have been reported so far to be causative for primary TRH deficiency (Mori et al. 1991; Prieto-Tenreiro et al. 2010).

Thyroid dysgenesis: TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5

Thyroid dyshormonogenesis: SLC26A4/PDS, SLC5A5/NIS, TPO, TG, IYD/DEHAL1, DUOXA2, and DUOX2

Central hypothyroidism: TSHB, IGSF1, TRH, TRHR and GNAS

Abnormal thyroid hormone metabolism: SECISBP2

Thyroid hormone resistance: THRA and THRB

Congenital hypothyroidism and neonatal diabetes mellitus: GLIS3

Pituitary hormone deficiency, combined: POU1F1, PROP1 and HESX1

Johanson-Blizzard syndrome: URB1

Allan-Herndon-Dudley syndrome: SLC16A2

See individual gene test descriptions for information on clinical features and molecular biology of gene products.

Most cases of congenital hypothyroidism (CH) don't have an identifiable cause, but in about 10%-15% of cases the conditions are caused by pathogenic variants in genes associated with thyroid gland development and function. The majority of cases (~80%) are due to pathogenic variants in genes associated with thyroid dysgenesis (TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5). The remaining ~15% are caused by defects in one of thyroid dyshormonogenesis-related genes (SLC26A4, SLC5A5, TPO, TG, IYD, DUOXA2, and DUOX2). Other causes appear to be very rare, including central hypothyroidism (TSHB, IGSF1, TRHR, THR and GNAS) and thyroid hormone resistance (THRA and THRB) (Péter and Muzsnai 2011; Nettore et al. 2013; Grasberger and Refetoff 2011). Over 85% of cases of thyroid hormone resistance (THR) are caused by THRB pathogenic variants. THRA pathogenic variants are a rare cause of THR (van Mullem et al. 2014; Tylki-Szymanska et al, 2015).

One gross deletion of the entire NKX2-5 gene was reported to be causative for congenital heart defects (Glessner et al. 2014).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes 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 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).