Congenital hypothyroidism
Gene: TSHR

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.

Created: 13 Feb 2017, 10:51 a.m.

Panel version: 0.43

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

PMID: 7528344
PMID: 22876533

Created: 10 Feb 2017, 11:59 p.m.

Panel version: 0.24

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