Congenital hypothyroidism

Gene: PRKAR1A

Green List (high evidence)

PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha)
EnsemblGeneIds (GRCh38): ENSG00000108946
EnsemblGeneIds (GRCh37): ENSG00000108946
OMIM: 188830, Gene2Phenotype
PRKAR1A is in 17 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Grey to Green after internal clinical discussion: 1 green review (from gene submitter). 4 cases of central hypothyroidism (CH) reported in PMID:22464250 with PRKAR1A variants. Given the gain-of-function effect reported in PMID:21651393, there may be a specific range of variants for this gene.
Created: 22 Feb 2017, 10:37 a.m.
Comment on mode of pathogenicity: PMID:21651393 report a gain-of-function mutation (R368X).
Created: 22 Feb 2017, 10:35 a.m.
PMID:21651393 (Linglart et al., 2011) report a truncating PRKAR1A mutation (c.1101C→T, (p.R368X) in 3 unrelated patients (2 Western European; 1 was of mixed descent (W. European and W. African).) with acrodysostosis and resistance to multiple hormones. They report that the mutated regulatory protein is deficient in dissociating from the catalytic subunit, and therefore is a gain-of-function effect.
Created: 21 Feb 2017, 3:47 p.m.
Michot et al. (2012, PMID:22464250) studied patients with acrodysostosis with hormone resistance and identified a heterozygous de novo c.1102C>T [p.Arg368Ter] variation in 4 cases and c.1117T>C [p.Tyr373His] in one case. All had evidence of hormone resistance, and 4 had clinical hypothyroidism.
Created: 21 Feb 2017, 2:48 p.m.
Comment on mode of inheritance: Mode of inheritance supported by OMIM.
Created: 20 Feb 2017, 11:56 a.m.

Nadia Schoenmakers (University of Cambridge)

Green List (high evidence)

Mutations in the same gene may cause Carney complex.
Created: 19 Feb 2017, 10:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Acrodysostosis, mild hormone resistance (TSH, PTH, GPCR-cAMP signalling hormones

Publications

  • Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, Motte E, Pinto G, Chanson P, Bougnères P, Clauser E, Silve C. N Engl J Med. 2011 Jun 9
  • 364(23):2218-26.

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

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

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

22 Feb 2017, Gel status: 0

Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

Mode of pathogenicity for PRKAR1A was changed to Other - please provide details in the comments

21 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PRKAR1A were set to 21651393; 22464250

20 Feb 2017, Gel status: 0

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for PRKAR1A was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

20 Feb 2017, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PRKAR1A were set to Acrodysostosis, mild hormone resistance (TSH, PTH, GPCR-cAMP signalling hormones; Acrodysostosis 1, with or without hormone resistance, 101800

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PRKAR1A were set to 21651393

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PRKAR1A were set to 21651393

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PRKAR1A were set to 21651393;

20 Feb 2017, Gel status: 0

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PRKAR1A were set to 21651393; 26416826 (2015 review)

19 Feb 2017, Gel status: 0

Added New Source

Nadia Schoenmakers (University of Cambridge)

PRKAR1A was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Literature

19 Feb 2017, Gel status: 0

Created

Nadia Schoenmakers (University of Cambridge)

PRKAR1A was created by [email protected]