Congenital hypothyroidism

Gene: OTX2

Green List (high evidence)

OTX2 (orthodenticle homeobox 2)
EnsemblGeneIds (GRCh38): ENSG00000165588
EnsemblGeneIds (GRCh37): ENSG00000165588
OMIM: 600037, Gene2Phenotype
OTX2 is in 16 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Grey to Green: 1 Green review (from gene submitter). 4 cases in total reporting missense mutations in CPHD patients, including the case in Del Blanco et al (PMID:22715480) where the unaffected father also carries the Pro134Arg variant. Functional studies in both PMID:27299576 and PMID:18728160. OTX2 is in OMIM phenotypic series with other CPHD genes.
Created: 22 Feb 2017, 11:22 a.m.
Added 'missense' tag because missense mutations only reported in the 3 papers described.
Created: 22 Feb 2017, 11 a.m.
Shimada et al., 2016 (PMID:27299576) report a R89P missense mutation in OTX2 in a CPHD patient. Full text of the article is unavailable.
Created: 21 Feb 2017, 1:53 p.m.
Del Blanco et al. 2012, (PMID:22715480) report a Dutch Caucasian male born from non-consanguineous parents, with combined pituitary hormone deficiency, and where central hypothyroidism (CH) was detected at age 9. The proband carried a heterozygous missense Pro134Arg mutation in OTX2. Note that this mutation was inherited from the phenotypically normal father.
Created: 21 Feb 2017, 1:52 p.m.
PMID:18728160 (Diaczok et al, 2008) describe 2 unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. A novel heterozygous OTX2 mutation (N233S) was identified. Mouse functional studies point to N233S acting as a dominant negative.
Created: 21 Feb 2017, 1:19 p.m.
OTX2 is an early pituitary transcription factor. Mutations in early or late pituitary transcription factors may cause central hypothyroidism (CH), a particular hypothyroid condition due to an insufficient stimulation by TSH of an otherwise normal thyroid gland. In these cases, CH does not occur in isolation, but is one of the evolving pituitary hormone deficiencies [PMID:26416826].
Created: 21 Feb 2017, 11:33 a.m.
Comment on mode of inheritance: Mode of inheritance confirmed by OMIM.
Created: 20 Feb 2017, 11:19 a.m.

Mode of pathogenicity
Other

Nadia Schoenmakers (University of Cambridge)

Green List (high evidence)

Highly variable pituitary and ocular phenotype
Created: 19 Feb 2017, 10:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
GH, TSH, ACTH, LH, FSH deficiency, Anophthalmia Retinal dystrophy, normal or hypoplastic anterior pituitary, ectopic posterior pituitary

Publications

  • Dateki S, Fukami M, Sato N, Muroya K, Adachi M & Ogata T 2008 OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. Journal of Clinical Endocrinology and Metabolism 93 3697–3702. (doi:10.1210/jc.2008-0720)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
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
OMIM
600037
Clinvar variants
Variants in OTX2
Penetrance
Complete
Publications
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.

22 Feb 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for OTX2 were set to GH, TSH, ACTH, LH, FSH deficiency; Anophthalmia Retinal dystrophy; normal or hypoplastic anterior pituitary; ectopic posterior pituitary; Pituitary hormone deficiency, combined, 6, 613986

22 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).

20 Feb 2017, Gel status: 0

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for OTX2 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for OTX2 were set to 18628516; 26416826 (2015 review)

20 Feb 2017, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for OTX2 were set to GH, TSH, ACTH, LH, FSH deficiency, Anophthalmia Retinal dystrophy, normal or hypoplastic anterior pituitary, ectopic posterior pituitary; Pituitary hormone deficiency, combined, 6, 613986

19 Feb 2017, Gel status: 0

Added New Source

Nadia Schoenmakers (University of Cambridge)

OTX2 was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Literature

19 Feb 2017, Gel status: 0

Created

Nadia Schoenmakers (University of Cambridge)

OTX2 was created by [email protected]