Description
Congenital hypothyroidism or thyroid agenesis eligibility statement:

Congenital hypothyroidism inclusion criteria (41912)
Congenital Hypothyroidism defined biochemically as: 
Primary CH: neonatal or early onset elevated TSH with subnormal or normal thyroid hormone levels
Central CH: neonatal or early onset subnormal thyroid hormone levels with normal or subnormal TSH 

Preferred inclusion criteria – cases from multicase families or consanguineous backgrounds or (in primary CH) with additional extra-thyroidal features.

Congenital hypothyroidism exclusion criteria (41912)
A high likelihood that the phenotype is completely explained by an acquired aetiology (eg autoimmunity, maternal autoantibodies, iodine deficiency)
A pathogenic mutation in a known causative gene which completely explains the phenotype.

Prior genetic testing guidance (41912)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Congenital hypothyroidism prior genetic testing genes (41912)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: 
Consideration of FOXE1, GNAS, SLC26A4, TSHR, TPO, DUOX2, TG

Closing statement (41912)
These requirements will be kept under continual review during the main programme and may be subject to change.

2 reviewers

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Nadia Schoenmakers (University of Cambridge)

    Group: GeCIP domain
    Workplace: Research lab

29 Entities

27 reviewed, 24 green

List Entity Reviews Mode of inheritance Details
29 Entitiess
Green Green List (high evidence)
15q11q13 recurrent (PWS/AS) region (BP1-BP3, Class 1) Loss
ISCA-37404-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • microcephaly
  • 105834
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
Tags
Green Green List (high evidence)
15q11q13 recurrent (PWS/AS) region (BP2-BP3, Class 2) Loss
ISCA-37478-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • microcephaly
  • Developmental delay, muscle weakness
  • Mental retardation
  • Angelman syndrome
  • 176270
  • Prader-Willi syndrome
  • 105830
Tags
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
1 review
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
Phenotypes
  • Pseudohypoparathyroidism Ia, 103580 (Hypothyroidism)
Tags
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
  • Panhypopiuitarism
  • GH and evolving TSH, ACTH, LH/FSH deficiency
  • septo-optic dysplasia
  • anterior pituitary, ectopic posterior pituitary
  • agenesis of corpus callous
  • optic nerve hypoplasia
  • Pituitary hormone deficiency, combined, 5, 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)
IYD
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
Phenotypes
  • Congenital hypothyroidism
  • Thyroid dyshormonogenesis 4, 274800
  • goitre
  • childhood/adolescent onset hypothyroidism
  • normal iodide organification
  • raised urinary MIT and DIT
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
2 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, 1, 613038 (Hypopthyroidism)
  • 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)
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)
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)
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
2 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
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)
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)
TBL1X
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 Amber
  • Literature
Phenotypes
  • isolated mild-moderate central hypothyroidism
Tags
  • missense
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
  • GH,TSH, ACTH, LH, FSH deficiency, variable mental retardation, undescended posterior pituitary, anterior pituitary hypoplasia, or persistence of the craniopharyngeal canal
Tags

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