Congenital hypothyroidism (Version 2.18)

The latest signed off version for the GMS is v2.2. The current version, shown here, may differ from the signed-off version.

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

10 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

37 Entities

37 reviewed, 30 green

List	Entity	Reviews	Mode of inheritance	Details
Filter Entities 37 Entitiess
Green 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 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 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 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 Green List (high evidence)	GNAS	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)	Sources Eligibility statement prior genetic testing Expert Review Green 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 Q4_22_MOI
Green 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Green List (high evidence)	TPO	2 reviews 1 green	BIALLELIC, autosomal or pseudoautosomal	Sources Eligibility statement prior genetic testing Expert Review Green Illumina TruGenome Clinical Sequencing Services UKGTN Phenotypes Congenital hypothyroidism Thyroid dyshormonogenesis 2A, 274500 TDH2A Iodide organification defect goitre Tags monogenic-polygenic
Green 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 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 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 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 Amber List (moderate evidence)	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 Amber Phenotypes microcephaly 105834 Developmental delay, muscle weakness Mental retardation Angelman syndrome 176270 Prader-Willi syndrome Tags
Amber 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 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 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 Red List (low evidence)	POLR2C	2 reviews	MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted	Sources Expert Review Red Literature Phenotypes hypothyroidism, MONDO:0005420 Tags
Red 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

Major version comments

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.

Congenital hypothyroidism (Version 2.18)

10 reviewers

37 Entities

37 reviewed, 30 green

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