Congenital hypothyroidism
Gene: PRKAR1AComment 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.
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
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.
This gene has been classified as Green List (High Evidence).
Mode of pathogenicity for PRKAR1A was changed to Other - please provide details in the comments
Publications for PRKAR1A were set to 21651393; 22464250
Mode of inheritance for PRKAR1A was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for PRKAR1A were set to Acrodysostosis, mild hormone resistance (TSH, PTH, GPCR-cAMP signalling hormones; Acrodysostosis 1, with or without hormone resistance, 101800
Publications for PRKAR1A were set to 21651393
Publications for PRKAR1A were set to 21651393
Publications for PRKAR1A were set to 21651393;
Publications for PRKAR1A were set to 21651393; 26416826 (2015 review)
PRKAR1A was added to Congenital hypothyroidism or thyroid agenesispanel. Sources: Literature
PRKAR1A was created by [email protected]