1. Panels
  2. Congenital hypothyroidism
The latest signed off version for the GMS is v3.0. The current version, shown here, may differ from the signed-off version.

Congenital hypothyroidism (Version 3.3)

Level 2: Endocrinology

Relevant disorders: Congenital hypothyroidism or thyroid agenesis, R145
Panel types: Rare Disease 100K, GMS Rare Disease Virtual, GMS Rare Disease, GMS signed-off
Latest signed off version: v3.0 (30 Apr 2025)
Previously signed off versions: v2.2
Previous code: 5763f2938f620350a1996046
Description
This panel is used for clinical indication 'R145 Congenital hypothyroidism', and can also be applied as a virtual panel in the analysis of genome or exome data in the NHS Genomic Medicine Service.

Further information on the testing criteria and any overlapping clinical indications can be found within (https://www.england.nhs.uk/publication/national-genomic-test-directories/)  under 'R145 Congenital hypothyroidism'.

A version of this panel has been signed off under NHS Genomic Medicine Service governance (see 'Latest signed off version' in the panel header information).

This panel will continue to be curated based on external reviews and Genomics England curation. New changes will be reflected in an increase to the minor version of the panel and details of these can be viewed in the 'Panel Activity' page. Periodically, these changes will be reviewed by a NHS Genomic Medicine Service evaluation process. The content that is agreed for the GMS panels will be reflected in an updated signed off version number. 

CNVs, STRs and genes encoded by the mitochondrial genome may not be routinely included in the analysis where the panel is NOT delivered by WGS. Please contact your Genomic Laboratory Hub for information regarding specific queries.

This panel was originally developed for the 100,000 Genomes Project and is still being used for participants in the project. For the rare disease eligibility criteria refer to: https://www.genomicsengland.co.uk/rarediseasecriteria100K

19th Dec 2018: additional Green genes from the Hyperthyroidism gene panel (Version 1.6, code 1.6) were added to this panel: SECISBP2, SLC16A2, THRB.
Panel Activity

11 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Nadia Schoenmakers (University of Cambridge)

    Group: GeCIP domain
    Workplace: Research lab

  • Eleanor Williams (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Zornitza Stark (Australian Genomics)

    Group: Other
    Workplace: Other clinical service

  • Ivone Leong (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS diagnostic lab

  • Arina Puzriakova (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Adam Gunning (Exeter Genomics Laboratory)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS diagnostic lab

38 Entities

38 reviewed, 30 green

List Entity Reviews Mode of inheritance Details
38 Entitiess
Green List (high evidence)
DUOX2
2 reviews
1 green 		BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Thryoid dyshormonogenesis 6, 607200
  • permanent congenital hypothyroidism
  • transient congenital hypothyroidism
  • eutopic gland-in-situ
  • goitre
  • borderline congenital hypothyroidism
  • iodide organification defect
Tags
  • monogenic-polygenic
Green List (high evidence)
DUOXA2
2 reviews
1 green 		BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
Phenotypes
  • Thyroid dyshormonogenesis 5, 274900
  • HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 5
  • eutopic gland-in-situ
  • mild congenital hypothyroidism
  • transient congenital hypothyroidism
Tags
  • deletions
  • monogenic-polygenic
Green List (high evidence)
FOXE1
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • UKGTN
Phenotypes
  • congenital hypothyroidism
  • Bamforth Lazarus syndrome, 241850 (hypothyroidism)
  • Hypothyroidism, Thyroidal Or Athyroidal, With Spiky Hair And Cleft Palate, 241850
  • thyroid agenesis
  • cleft palate
  • spiky hair
  • choanal atresia
Tags
Green List (high evidence)
GLIS3
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Diabetes mellitus, neonatal, with congenital hypothyroidism, 610199
  • neonatal non-autoimmune diabetes mellitus
  • severe congenital hypothyroidism
  • variable cholestasis
  • hepatic fibrosis
  • congenital glaucoma
  • polycystic kidneys
  • dysmorphic facies
  • sensorineural deafness
Tags
Green List (high evidence)
GNAS
3 reviews
 MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Pseudohypoparathyroidism Ia, OMIM:103580
  • pseudohypoparathyroidism type 1A, MONDO:0007078
  • Pseudohypoparathyroidism Ib, OMIM:603233
  • pseudohypoparathyroidism type 1B, MONDO:0011301
  • Pseudohypoparathyroidism Ic, OMIM:612462
  • pseudohypoparathyroidism type 1C, MONDO:0012911
Tags
Green List (high evidence)
HESX1
2 reviews
1 green 		BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Growth hormone deficiency with pituitary anomalies, OMIM:182230
  • Pituitary hormone deficiency, combined, 5, OMIM:182230
  • Septooptic dysplasia, OMIM:182230
Tags
Green List (high evidence)
IGSF1
2 reviews
1 green 		X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • central hypothyroidism
  • hypoprolactinaemia
  • GH deficiency
  • macroorchidism
  • Hypothyroidism, central, and testicular enlargement, 300888
Tags
Green List (high evidence)
IRS4
2 reviews
1 green 		X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • East of England GLH
  • Expert Review Green
Phenotypes
  • Congenital central hypothyroidism
Tags
Green List (high evidence)
IYD
3 reviews
1 green 		BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
Phenotypes
  • Thyroid dyshormonogenesis 4, OMIM:274800
Tags
Green List (high evidence)
LHX3
2 reviews
 BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • GH, TSH, LH, FSH, PRL deficiency
  • limited neck rotation
  • short cervical spine
  • sensorineural deafness
  • anterior pituitary may be normal, hypoplastic or enlarged
  • Pituitary hormone deficiency, combined, 3, 221750
Tags
Green List (high evidence)
LHX4
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • GH, TSH, ACTH, variable gonadotrophin deficiencies
  • cerebellar abnormalities
  • anterior pituitary hypoplasia
  • etopic posterior pituitary
  • Pituitary hormone deficiency, combined, 4, 262700
Tags
Green List (high evidence)
NKX2-1
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Choreoathetosis, hypothyroidism, and neonatal respiratory distress, 610978
  • Choreoathetosis And Congenital Hypothyroidism With Or Without Pulmonary Dysfunction, 610978
  • CAHTP
  • Neurological abnormalities
  • benign hereditary chorea
  • neonatal respiratory distress syndrome
  • recurrent respiratory infections
Tags
Green List (high evidence)
OTX2
3 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • GH, TSH, ACTH, LH, FSH deficiency
  • Anophthalmia Retinal dystrophy
  • normal or hypoplastic anterior pituitary
  • ectopic posterior pituitary
  • Pituitary hormone deficiency, combined, 6, 613986
Tags
  • missense
Green List (high evidence)
PAX8
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Hypothyroidism, Congenital, Nongoitrous, 2, 218700
  • Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia, 218700
  • urogenital tract malformations
  • thyroid hypoplasia
  • thyroid dysgenesis
  • eutopic gland-in-situ
Tags
Green List (high evidence)
POU1F1
2 reviews
1 green 		BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
Phenotypes
  • Pituitary hormone deficiency, combined or isolated, 1, OMIM:613038
  • Congenital hypothyroidism
Tags
Green List (high evidence)
PRKAR1A
2 reviews
1 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Acrodysostosis, mild hormone resistance (TSH, PTH, GPCR-cAMP signalling hormones
  • Acrodysostosis 1, with or without hormone resistance, 101800
Tags
Green List (high evidence)
PROP1
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • GH, TSH, LH, FSH, PRL deficiency with variable age of onset, evolving ACTH deficiency
  • Commonest cause of combined pituitary hormone deficit without extra pituitary manifestations
  • Hypoplastic or normal anterior pituitary although there have been reports of an enlarged anterior pituitary at initial scanning in childhood with spontaneous involution over time
  • Pituitary hormone deficiency, combined, 2, 262600
Tags
Green List (high evidence)
SECISBP2
2 reviews
 BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Short stature-delayed bone age due to thyroid hormone metabolism deficiency
  • Selenocysteine insertion sequence binding protein 2 (SBP2) defect
  • Abnormal thyroid hormone metabolism
  • Thyroid hormone metabolism, abnormal, 609698
  • THYROID HORMONE METABOLISM, ABNORMAL
Tags
Green List (high evidence)
SLC16A2
2 reviews
 X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
Phenotypes
  • Allan-Herndon-Dudley syndrome, OMIM:300523
Tags
  • treatable
Green List (high evidence)
SLC26A4
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Other
Phenotypes
  • Pendred syndrome, 274600 (congenital deafness and thyroid goitre)
  • Sensorineural deafness
  • enlarged vestibular aqueduct
  • Mondini defect
  • partial iodide organification defect
  • goitre
  • mild hypothyroidism
Tags
  • monogenic-polygenic
  • treatable
Green List (high evidence)
SLC26A7
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • East of England GLH
  • Expert Review Green
Phenotypes
  • Primary congenital hypothyroidism (dyshormonogenesis)
Tags
  • gene-checked
Green List (high evidence)
SLC5A5
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
Phenotypes
  • Thyroid dyshormonogenesis 1, 274400
  • HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 1
  • Apparent athyreosis on nuclear medicine scan
  • goitre
  • childhood onset hypothyroidism
Tags
Green List (high evidence)
TBL1X
4 reviews
2 green 		X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • isolated mild-moderate central hypothyroidism
  • Hypothyroidism, congenital, nongoitrous, 8, 301033
Tags
  • missense
Green List (high evidence)
TG
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Thyroid dyshormonogenesis 3, 274700
  • TDH3
  • low thyroglobulin, goitre
Tags
  • monogenic-polygenic
Green List (high evidence)
THRA
4 reviews
1 red 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Congenital hypothyroidism or thyroid agenesis
  • Hypothyroidism, Congenital, Nongoitrous, 6, 614450
  • Hypothyroidism, congenital, nongoitrous, 6, 614450
  • Resistance to thyroid hormone
  • skeletal dysplasia
  • growth retardation
  • macrocephaly
  • neurodevelopmental delay
  • constipation
  • delayed dentition
  • macrocytic anaemia
Tags
  • treatable
Green List (high evidence)
THRB
2 reviews
 BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Resistance to thyroid hormone (RTH)
  • THYROID HORMONE UNRESPONSIVENESS
  • 145650
  • REFETOFF SYNDROME
  • PRTH
  • Thyroid hormone resistance, autosomal recessive, 274300
  • Refetoff syndrome
  • THYROID HORMONE RESISTANCE, SELECTIVE PITUITARY
  • thyroid hormone unresponsiveness, generalized RTH, RTH beta
  • Thyroid hormone resistance, 188570
  • THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT
  • THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE
  • Thyroid Hormone Resistance (monoallelic)
  • Thyroid hormone resistance, selective pituitary, 145650
  • HYPERTHYROIDISM, FAMILIAL, DUE TO INAPPROPRIATE THYROTROPIN SECRETION
  • GRTH
  • Thyroid Hormone Resistance, Selective Pituitary
  • THYROID HORMONE UNRESPONSIVENESS HYPERTHYROXINEMIA, FAMILIAL EUTHYROID, SECONDARY TO PITUITARY AND PERIPHERAL RESISTANCE TO THYROID HORMONES
Tags
  • treatable
Green List (high evidence)
TPO
3 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
Phenotypes
  • Thyroid dyshormonogenesis 2A, OMIM:274500
Tags
  • monogenic-polygenic
Green List (high evidence)
TRHR
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • mild-moderate isolated central hypothyroidism
  • absent TSH and prolactin response to TRH
  • Thyrotropin-releasing hormone resistance, generalized
Tags
Green List (high evidence)
TSHB
2 reviews
1 green 		BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
Phenotypes
  • Congenital hypothyroidism
  • Hypothryoidism, congenital, nongoitrous 4, 275100
  • severe isolated central hypothyroidism
Tags
Green List (high evidence)
TSHR
2 reviews
1 green 		BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Congenital hypothyroidism
  • Hypothyroidism, Congenital, Nongoitrous, 1, 275200
  • Hypothyroidism, congenital, nongoitrous, 1 275200
  • TSH resistance
  • thyroid hypoplasia
  • subclinical hypothyroidism
  • thyroid dysgenesis
  • eutopic gland-in-situ
  • compensated hypothryoidism
Tags
Amber List (moderate evidence)
CDCA8
2 reviews
 BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Amber
  • Literature
  • NHS GMS
Phenotypes
  • Congenital hypothyroidism
  • thyroid dysgenesis
  • No OMIM number
Tags
Amber List (moderate evidence)
15q11q13 recurrent (PWS/AS) region (BP2-BP3, Class 2) Loss
ISCA-37478-Loss
Region
1 review
 MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Amber
Phenotypes
  • microcephaly
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
  • 105830
Tags
Amber List (moderate evidence)
NKX2-5
2 reviews
1 red 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypothyroidism, congenital nongoitrous, 5, 225250
  • thyrioid ectopy, thyroid agenesis, congenital heart disease
Tags
Amber List (moderate evidence)
TUBB1
2 reviews
 BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • East of England GLH
  • Expert Review Amber
Phenotypes
  • Primary congenital hypothyroidism, thyroid dysgenesis, macroplatelets
Tags
Red List (low evidence)
POLR2C
2 reviews
 MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • hypothyroidism, MONDO:0005420
Tags
Red List (low evidence)
SOX3
2 reviews
1 green 		X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123
  • Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
  • Panhypopituitarism, X-linked, OMIM:312000
  • Panhypopituitarism, X-linked, MONDO:0010712
Tags
No list
15q11q13 recurrent (PWS/AS) region (BP1-BP3, Class 1) Loss
ISCA-37404-Loss
Region
2 reviews
 MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Removed
Phenotypes
  • microcephaly
  • 105834
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
Tags
  • curated_removed
No list
Short tandem repeat, Thyroid-specific
STRTS
Region
3 reviews
2 green 		MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Literature
  • NHS GMS
Phenotypes
  • Congenital hypothyroidism
  • Small thyroid (in children)
  • Multinodular goitre (with age, if untreated)
  • Elevated serum TSH
Tags
  • curated_removed

Major version comments

  • 2025-04-30 16:27 Arina Puzriakova (Genomics England Curator) promoted panel to 3.0
    The content of this panel has been updated in accordance with changes agreed with the NHS Genomic Medicine Service. The panel was promoted to the next major version (3.0) following this.

    2019-07-31 13:52 Ivone Leong (Genomics England Curator) promoted panel to 2.0
    The content of this panel (version 1.27) was signed off under NHS Genomic Medicine Service governance on (31/07/2019). The panel was promoted to the next major version (version 2.0) as a result of this.

    22 February 2017: Promoted to Version 1. Reviews were assessed, and panel was revised according to expert review and additional curation. After discussion with the reviewer and in-house clinicians, it was agreed to include the genes for 'combined pituitary hormone deficiency' (CPHD) on the panel, since patients can present with central hypothyroidism (CH). In these cases, CH does not occur in isolation, but is one of the evolving pituitary hormone deficiencies.

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  • Green and Amber Genes
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