The function of PRKAR1A
The PRKAR1A gene encodes one of the proteins, known as type I alpha, that make up the enzyme protein kinase A (PKA). PKA is involved in several biological processes including cell growth.
How do disease-causing variants in PRKAR1A cause CNC?
Disease-causing variants in PRKAR1A cause the PKA enzyme to be active more frequently than normal. Tumor formation in patients with CNC is a result of uncontrolled PKA activity. Parents with a disease-causing variant in PRKAR1A have a 50% chance of passing the variant to their child. Almost all patients with a disease-causing variant in PRKAR1A will develop CNC.
Genetic testing
Disease-causing variants are detected using Sanger sequencing analysis of the PRKAR1A gene. If no pathogenic variants are detected, copy number variant and gene-targeted deletion analysis should be performed to detect exon or whole-gene deletions or duplications which may not have been detected by Sanger sequencing. After ruling out pathogenic PRKAR1A variants, other genetic causes of CNC can be explored (i.e. PRKACA, PRKACB). Parents of affected children should be tested for pathogenic variants in PRKAR1A to determine if the variant was inherited or occurred sporadically (de novo).