Congenital hypothyroidism

Gene: THRA

Green List (high evidence)

THRA (thyroid hormone receptor, alpha)
EnsemblGeneIds (GRCh38): ENSG00000126351
EnsemblGeneIds (GRCh37): ENSG00000126351
OMIM: 190120, Gene2Phenotype
THRA is in 7 panels

4 reviews

Ellen McDonagh (Genomics England Curator)

Added the 'treatable' tag to this gene, after feedback from Krish Chatterjee and Carla Moran, Institute of Metabolic Science, Cambridge; thyroxine can be used as a treatment for resistance to thyroid hormone alpha due to THRA defects.
Created: 8 Aug 2018, 7:49 a.m.

Louise Daugherty (Genomics England Curator)

Report variants in this gene as part of diagnostic practice : Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge (From expert review Krishna Chatterjee and Carla Moran)
Created: 15 Mar 2017, 4:50 p.m.
Comment on publications: From reviewer recommendation PMID:27381958 added Resistance to Thyroid Hormone α-Emerging Definition of a Disorder of Thyroid Hormone Action by Carla Moran and Krishna Chatterjee. J Clin Endocrinol Metab. 2016 Jul;101(7):2636-9. doi: 10.1210/jc.2016-2317.
Created: 15 Mar 2017, 4:44 p.m.
Comment when marking as ready: gene has been assessed for involvement in Resistance to thyroid hormone according to expert reviews and further curation
Created: 15 Mar 2017, 3:47 p.m.
Comment on list classification: Changed status from Red to Green due to evidence in the literature and expert review comments
Created: 15 Mar 2017, 3:26 p.m.
Comment on publications: PMID: 27144938 large case study that shows the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.
Created: 15 Mar 2017, 3:24 p.m.
Comment on publications: To date more than 10 unrelated families (15 affecteds) with THRA defects giving rise to resistance to thyroid hormone alpha have been described. Examples include: PMID:22168587 (1 affected), 22494134 (1 family, 2 affecteds), 23940126 (1 affected, 25670821 (5 unrelated affecteds); 27144938 (3 unrelated families, 10 affecteds)
Created: 15 Mar 2017, 3:22 p.m.

Variants in this GENE are reported as part of current diagnostic practice

Rebecca Foulger (Genomics England curator)

Comment when marking as ready: >3 unrelated cases (including a de novo mutation), confirmed DD-G2P gene, and included on panel since established cause of hypothyroidism.
Created: 14 Feb 2017, 5:28 p.m.
Comment on list classification: Updated rating from Amber to Green based on DD-G2P confirmation and comment from Helen Brittain: Cases may not fulfill the recruitment criteria in view of high normal / elevated T3 owing to the resistance (related to the receptor mutations), however in the reported cases the T4 has been low-normal and TSH normal which could reach inclusion. Include as it is an established cause of hypothyroidism but accept that if the referrers strictly adhere to the inclusion criteria this may lead to some cases not being recruited.
Created: 14 Feb 2017, 5:25 p.m.
Comment on mode of inheritance: Mode of inheritance confirmed by OMIM and G2P.
Created: 13 Feb 2017, 12:52 p.m.
Confirmed DD-G2P gene for Hypothyroidism, congenital, nongoitrous, 6 (MIM:614450).
Created: 13 Feb 2017, 12:49 p.m.

Nadia Schoenmakers (University of Cambridge)

Red List (low evidence)

This gene is associated with resistance to thyroid hormone. Cases fulfilling the recruitment criteria for congenital hypothyroidism are unlikely to have mutations in this gene.
Created: 11 Feb 2017, 12:14 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Resistance to thyroid hormone; skeletal dysplasia; growth retardation; macrocephaly; neurodevelopmental delay; constipation; delayed dentition; macrocytic anaemia

Publications

Details

Mode of Inheritance
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
OMIM
190120
Clinvar variants
Variants in THRA
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

19 Dec 2018, Gel status: 3

Added Tag

Ellen McDonagh (Genomics England Curator)

Tag treatable tag was added to gene: THRA.

19 Dec 2018, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene: THRA were set to 22168587; 23940126

22 Feb 2017, Gel status: 4

panel promoted to version 1

Rebecca Foulger (Genomics England curator)

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.

14 Feb 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

14 Feb 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for THRA were set to 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

14 Feb 2017, Gel status: 4

Set publications

Rebecca Foulger (Genomics England curator)

Publications for THRA were set to 22168587; 23940126

14 Feb 2017, Gel status: 4

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for THRA was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

14 Feb 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

13 Feb 2017, Gel status: 2

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for THRA was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

23 Jan 2017, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

THRA was added to Congenital hypothyroidism or thyroid agenesispanel. Source: Radboud University Medical Center, Nijmegen

23 Jan 2017, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene THRA were set to Congenital hypothyroidism or thyroid agenesis; Hypothyroidism, Congenital, Nongoitrous, 6, 614450

13 Oct 2016, Gel status: 1

Added New Source

Olivia Niblock (Genomics England Curator)

THRA was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: UKGTN

13 Oct 2016, Gel status: 0

Created

Olivia Niblock (Genomics England Curator)

THRA was created by oniblock