Congenital hypothyroidism (CH)

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.

Visit the NHS Genomic Test Directory 

Eligibility criteria for genomic tests can be found in the National Genomic Test Directory.

This lists the clinical specialties that would be expected to request for a given clinical indication and sets out which patients should be considered for testing.

All samples for genomic testing should be accompanied by a fully completed request form.

The request form should include as much clinical information about the patient or family member, family relationships and the requested test code (R number). All request forms must indicate either a specific disorder/gene(s) to be investigated or, a request to extract and store DNA.

This form should be used for the majority of test requests.

Please do not download and store this on your desktop or system. The form is regularly updated. Our recommendation is to save or bookmark a link to our website to ensure you are working with the most up-do-date version.

Download the latest version here: GMS Test Order Form v2.3

An appropriate discussion of genomic testing and the possible implications for a patient and their family members must take place before testing is requested.

It is the referring clinician’s responsibility to ensure that the patient/carer knows the purpose of the test and that the sample may be stored for future diagnostic testing. In submitting a sample with a request form, the clinician confirms that informed consent has been obtained for (a) testing and storage (indefinitely) (b) the use of this sample and the information generated from it to be shared with members of the donor’s family and their health professionals (if appropriate). The patient should be advised that the samples may be used anonymously for quality assurance and training purposes.

If stated as a requirement for a specific test, a record of this discussion must be retained within the patient record when a genomic test is ordered.

For more information please view the Consent and Confidentiality in Genomic Medicine guidelines from the Joint Committee on Medical Genetics.

Before sending samples for genomic testing, please ensure you follow the correct preparation and transport guidelines. This includes information on sample types, volumes, handling, labelling, and packaging standards.

For a full list of sample requirements and transport guidance, please visit the samples and transport page of the website. 

Turnaround times (TATs) for genomic tests are continually refined through ongoing reviews of testing standards.

Results will be returned to the email account or clinician listed on the request form.

Visit the results and turnaround page for more information.