Congenital hypothyroidism

Gene: TSHR

Green List (high evidence)

TSHR (thyroid stimulating hormone receptor)
EnsemblGeneIds (GRCh38): ENSG00000165409
EnsemblGeneIds (GRCh37): ENSG00000165409
OMIM: 603372, Gene2Phenotype
TSHR is in 6 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Plenty of cases of TSHR mutations causing hypothyroidism in OMIM and literature, from range of populations including French, Japanese and Welsh.
Created: 13 Feb 2017, 11:24 a.m.
Comment when marking as ready: One Green review plus Confirmed DD-G2P gene for hypothyroidism plus plenty of cases of TSHR mutations causing hypothyroidism. Updated MOI to include heterozygote carriers with subclinical/compensated hypothyroidism.
Created: 13 Feb 2017, 11:23 a.m.
Comment on mode of inheritance: Changed the mode of inheritance from 'biallelic' to 'both monoallelic and biallelic' to match Reviewer. Plus a number of papers (PMID:17526952, 14725684, 16060907) etc report that heterozygous mutations in TSHR cause Compensated hypothyroidism/subclinical hypothyroidism with raised thyroid-stimulating hormone (TSH) concentration plus normal T4 (thyroxine) levels; these patients show mild symptoms of hypothryoidism or are asymptomatic.
Created: 13 Feb 2017, 11:19 a.m.
Confirmed DD-G2P gene for Hypothyroidism, congenital, nongoitrous, 1, MIM:275200.
Created: 13 Feb 2017, 10:52 a.m.
Comment on phenotypes: TSHR variants are causative of both hypothyroidism (Hypothyroidism, congenital, nongoitrous, 1, 275200) and hyperthyroidism (Hyperthyroidism, familial gestational, 603373 and Hyperthyroidism, nonautoimmune, 609152).
Created: 13 Feb 2017, 10:43 a.m.

Nadia Schoenmakers (University of Cambridge)

Green List (high evidence)

Spectrum ranging from non-autoimmune hypertyrotropinaemia with ectopic gland-in-situ to severe CH with gland hypoplasia/apparent athyreosis. May have a ‘reset’ hypothalamic pituitary-thyroid axis such that it is difficult to normalize TSH without supraphysiological fT4 concentrations
Created: 10 Feb 2017, 11:59 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
TSH resistance; thyroid hypoplasia; subclinical hypothyroidism; thyroid dysgenesis; eutopic gland-in-situ

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Eligibility statement prior genetic testing
  • UKGTN
  • Illumina TruGenome Clinical Sequencing Services
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
OMIM
603372
Clinvar variants
Variants in TSHR
Penetrance
Complete
Publications
  • 7528344
  • 22876533
  • PMID:17526952 (Kanda et al., 2006) examine Japanese patients homozygous and heterozygous for the R450H mutation in the TSHR gene. Homozygous subjects displayed mild hypothyroidism/ Heterozygous patients also demonstrated hypothyroidism, but less severe than that of homozygous subjects.
  • PMID:14725684 (Park et al. 2004) suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia
  • 16060907 (Camilot et al., 2005 report subclinical hypothyroid subjects with heterozygous substitutions
  • 27525530 (Nicholas et al.,2016) identify a monogenic basis of disease.
Panels with this gene

History Filter Activity

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.

16 Feb 2017, Gel status: 4

Set publications

Rebecca Foulger (Genomics England curator)

Publications for TSHR were set to 7528344; 22876533; PMID:17526952 (Kanda et al., 2006) examine Japanese patients homozygous and heterozygous for the R450H mutation in the TSHR gene. Homozygous subjects displayed mild hypothyroidism/ Heterozygous patients also demonstrated hypothyroidism, but less severe than that of homozygous subjects.; PMID:14725684 (Park et al. 2004) suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia; 16060907 (Camilot et al., 2005 report subclinical hypothyroid subjects with heterozygous substitutions; 27525530 (Nicholas et al.,2016) identify a monogenic basis of disease.

13 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: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for TSHR were set to 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

13 Feb 2017, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for TSHR were set to 7528344; 22876533; PMID:17526952 (Kanda et al., 2006) examine Japanese patients homozygous and heterozygous for the R450H mutation in the TSHR gene. Homozygous subjects displayed mild hypothyroidism/ Heterozygous patients also demonstrated hypothyroidism, but less severe than that of homozygous subjects.; PMID:14725684 (Park et al. 2004) suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia; 16060907 (Camilot et al., 2005 report subclinical hypothyroid subjects with heterozygous substitutions.

13 Feb 2017, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for TSHR were set to 7528344; 22876533; PMID:17526952 (Kanda et al., 2006) examine Japanese patients homozygous and heterozygous for the R450H mutation in the TSHR gene. Homozygous subjects displayed mild hypothyroidism/ Heterozygous patients also demonstrated hypothyroidism, but less severe than that of homozygous subjects.; PMID:14725684 (Park et al. 2004) suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia; 16060907 (Camilot et al., 2005 report subclinical hypothyroid subjects with heterozygous substitutions.

13 Feb 2017, Gel status: 3

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for TSHR was changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

13 Feb 2017, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for TSHR were set to Congenital hypothyroidism; Hypothyroidism, Congenital, Nongoitrous, 1, 275200; Hypothyroidism, congenital, nongoitrous, 1 275200; TSH resistance; thyroid hypoplasia; subclinical hypothyroidism; thyroid dysgenesis; eutopic gland-in-situ

13 Feb 2017, Gel status: 3

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for TSHR was changed to BIALLELIC, autosomal or pseudoautosomal

13 Feb 2017, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for TSHR were set to Congenital hypothyroidism; Hypothyroidism, Congenital, Nongoitrous, 1, 275200; Hypothyroidism, congenital, nongoitrous, 1 275200; TSH resistance; thyroid hypoplasia; subclinical hypothyroidism; thyroid dysgenesis; eutopic gland-in-situ

13 Feb 2017, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for TSHR were set to 7528344; 22876533

13 Feb 2017, Gel status: 3

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for TSHR was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

23 Jan 2017, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

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

23 Jan 2017, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

TSHR was added to Congenital hypothyroidism or thyroid agenesispanel. Source: Eligibility statement prior genetic testing

23 Jan 2017, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene TSHR were set to Congenital hypothyroidism;Hypothyroidism, Congenital, Nongoitrous, 1, 275200

13 Oct 2016, Gel status: 2

Added New Source

Olivia Niblock (Genomics England Curator)

TSHR was added to Congenital hypothyroidism or thyroid agenesispanel. Source: UKGTN

13 Oct 2016, Gel status: 1

Added New Source

Olivia Niblock (Genomics England Curator)

TSHR was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Illumina TruGenome Clinical Sequencing Services

13 Oct 2016, Gel status: 0

Created

Olivia Niblock (Genomics England Curator)

TSHR was created by oniblock