Congenital hypothyroidism

Gene: PRKAR1A

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.

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.