Carney Complex (CNC) via the PRKAR1A Gene

Carney Complex (CNC) is a disorder that is characterized by skin pigment abnormalities, myxomas, endocrine overactivity or tumors, and schwannomas (Stratakis and Horvath 2012). This disorder had previously been called LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue naevi) or NAME (naevi, atrial myxomas, myxoid neurofibroma, and ephelides) (Rothenbuhler and Stratakis 2010). The most common skin pigment changes are lentigines, which are small benign pigmented spots on the skin with a clearly defined border. Both cutaneous and cardiac myxomas are also observed in individuals with CNC. Myxomas are tumors that are primarily connective tissue, which can occur in the skin, breast, oropharynx or the female genital tract. Cardiac myxomas occur at a young age and can obstruct blood flow leading to heart failure, and are one of the leading causes of CNC mortality. Other clinical manifestations of CNC include primary pigmented nodular adrenocortical disease (PPNAD), which is the most frequently observed tumor, found in approximately 25% of affected individuals. This causes periodic or atypical Cushing syndrome, where the body is exposed to prolonged exposure to cortisol leading to obesity, severe fatigue, weak muscles, high blood pressure, high blood sugar, irritability, and anxiety. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are found in almost all adult males, and multiple thyroid nodules are identified in approximately 75% of affected individuals. Acromegaly resulting from a growth hormone (GH)-producing adenoma and Psammomatous melanotic schwannoma (PMS) are identified in approximately 10% of affected individuals (Halászlaki et al. 2012; Stratakis and Horvath 2012). The median age of diagnosis is 20 years, and more than 700 cases worldwide are known (Stratakis and Horvath 2012).

Carney Complex (CNC) is an autosomal dominant disorder that has near complete penetrance by age 50 (Stratakis and Horvath 2012). It is caused by mutations in the PRKAR1A gene, which encodes a tumor suppressor that acts as a cyclic-AMP-dependent signaling molecule. The signaling molecule phosphorylates many downstream targets that are involved in transcription, metabolism, cell cycle progression and apoptosis (Rothenbuhler and Stratakis 2010). Approximately 70% of PRKAR1A causative mutations are inherited from an affected parent, and 30% of causative mutations are de novo. Most pathogenic variants result in protein loss of function, such as nonsense, and small insertions and deletions; causing nonsense mediated decay (Pan et al. 2010). Other causative mutations include missense variants and large deletions. Specific genotype-phenotype correlations have been observed with certain pathogenic variants, which may guide clinical management (Stratakis and Horvath 2012).

Pathogenic variants in the PRKAR1A gene can be detected via sequencing in ~60% of affected individuals (Stratakis and Horvath 2012).

Pathogenic variants in the PRKAR1A gene can be detected via large deletion testing in 2-21% of affected individuals (Stratakis and Horvath 2012; Salpea et al. 2014).

This test provides full coverage of all coding exons of the PRKAR1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.