NA = not applicable

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

In the largest study to date, 114 (62%) of 185 families studied had an identifiable PRKAR1A pathogenic variant [Bertherat et al 2009]. The variant detection frequency increases to 80% in individuals with Carney complex (CNC) presenting with Cushing syndrome caused by primary pigmented nodular adrenocortical disease (PPNAD) [Cazabat et al 2007].

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

In a study of 36 unrelated individuals with CNC who were negative for PRKAR1A single-nucleotide variants, two large PRKAR1A deletions were identified [Horvath et al 2008]. Of 51 individuals with CNC who were negative for other PRKAR1A pathogenic variants, 21.6% had a PRKAR1A deletion [Salpea et al 2014]. The deletions ranged from 328 bp to 3 Mb, affecting part or all of PRKAR1A; all deletions led to PRKAR1A haploinsufficiency.

Approximately 20% of families with CNC have been linked to 2p16 [Stratakis et al 1996].

Germline PRKACA duplications have been identified in five individuals (from four kindreds) with CNC who have adrenal tumors and Cushing syndrome [Beuschlein et al 2014]. In one of these kindreds, the duplication was inherited; in another individual, the duplication was de novo [Beuschlein et al 2014].

One individual with CNC had a germline rearrangement resulting in four copies of PRKACB [Forlino et al 2014]. PRKACB encodes the catalytic subunit Cβ of the cyclic AMP-dependent protein kinase A (PKA). Levels of Cβ and PKA activity were increased in the individual's lymphoblasts and fibroblasts; the authors propose that this is a CNC-causing gain-of-function variant.