Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment if untreated. CH is characterized by elevated levels of thyroid-stimulating hormone (TSH) resulting from reduced thyroid function.
In 80 to 85% of cases, congenital hypothyroidism is associated with, and presumably is a consequence of, thyroid dysgenesis. In these cases, the thyroid gland can be absent (agenesis), ectopically located, and/or severely reduced in size (hypoplasia). Thyroid dysgenesis is due to pathogenic variants in the FOXE1, GLIS3, NKX2-1, PAX8, THRA and TSHR genes.
Inborn errors of thyroid hormone biosynthesis (dyshormonogenesis) account for 10-15% of cases. Thyroid dyshormonogenesis is caused by pathogenic variants in the DUOX2, DUOXA2, GNAS, SLC5A5, SLC26A4, SLC26A7, TG, TPO, TSHR and IYD genes (Persani et al 2018 PMID: 30086865).
Pathogenic variants in HESX1, LHX3, LHX4, OTX2, POU1F1, PROP1, cause Combined Pituitary Hormone Deficiency which can present as Congenital Hypothyroidism.
Pathogenic variants in IGSF1, IRS4, PRKAR1A, TSHB, TRHR and TBL1X have been reported in patients with isolated central hypothyroidism (Joustra et al 2016 PMID:26840047; Heinen et al 2018 PMID: 30061370).
SLC16A2 encodes a triiodothyronine (T3) transporter. Pathogenic variants in this gene cause Allan–Herndon–Dudley syndrome, an X-linked disorder characterised by moderate to severe intellectual disability and problems with movement. Males have abnormally high 3,3′,5′-triiodothyronine (T3), low to normal free tetraiodothyronine (T4) levels, and normal to slightly elevated thyroid stimulating hormone (TSH) levels (Remerand et al 2019 PMID: 31410843).
Thyroid hormone resistance is cause by pathogenic variants in THRA and THRB (Singh and Yen 2017 PMID: 28932413).
The Congenital Hypothyroidism panel contains the following genes: DUOX2, DUOXA2, FOXE1, GLIS3, GNAS, HESX1, IGSF1, IRS4, IYD, LHX3, LHX4, NKX2-1, OTX2, PAX8, POU1F1, PRKAR1A, PROP1, SECISBP2, SLC16A2, SLC26A4, SLC26A7, SLC5A5, TBL1X, TG, THRA, THRB, TPO, TRHR, TSHB and TSHR.
NHSE test directory code: R145 Congenital hypothyroidism. Testing criteria can be found on this webpage: https://www.england.nhs.uk/publication/national-genomic-test-directories/.
The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.