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PRKAR1A Gene Mutation

Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. CNC may be evident at birth, but the median age of diagnosis is 20 years.

Major diagnostic criteria include:

  • Spotty skin pigmentation involving lips, conjunctiva and inner or outer canthi, vaginal and penile mucosal
  • Cutaneous and mucosal myxoma
  • Cardiac myxoma
  • Breast myxomatosis
  • Primary pigmented nodular adrenocortical disease
  • Acromegaly due to growth hormone (GH) adenoma
  • Large-cell calcifying Sertoli cell tumor
  • Thyroid cancer
  • Psammomatous melanotic schwannomas
  • Blue nevus, epithelioid blue nevus
  • Breast ductal adenoma
  • Osteochondromyxoma

CNC is caused by mutations in the PRKAR1A gene, which is located on chromosome 17q23-q24 and codes for a cAMP-dependent protein kinase type I-alpha regulatory subunit. More than 100 different mutations have been identified. Mutations are spread along the entire coding sequence and include single base substitutions and small deletions, insertions, or combined rearrangements. In addition, several relatively large deletions have been reported. To date, only three mutations have been found in more than three unrelated pedigrees: c.82C>T, c.491_492delTG, and c.709-2_709-7 delATTTTT. 

The vast majority of mutations (>80%) result in creation of a new premature stop codon by nonsense or frameshift changes upstream of the last exon. Such mutations predict degradation of the mutant mRNAs through a mechanism of nonsense-mediated decay. A relatively small proportion of unique missense and frameshift mutations results in the expression of an altered protein. PRKAR1A appears to function as a classic tumor suppressor gene in tumors from individuals with Carney complex. In CNC tumors, loss of the PRKAR1A protein leads to enhanced intracellular signaling by protein kinase A.

The diagnosis of CNC usually relies on clinical diagnostic criteria. CNC is inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with CNC have an affected parent; approximately 30% have a de novo mutation. Each child of an individual with CNC has a 50% chance of inheriting the mutation.

Gene Sequence analysis of the PRKAR1A coding region has a mutation detection rate of approximately 70%. The 10 coding exons and splice sites of the PRKAR1A gene are screened by bi-directional sequence analysis. If no mutation is found by sequencing, targeted array CGH analysis is used to detect deletions or duplications of one or more exons.

Consideration of molecular genetic testing of young at-risk family members is appropriate for guiding medical management. Predictive testing for young at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

When a clinically diagnosed relative has undergone molecular genetic testing and is found to have a mutation in PRKAR1A, molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members.

When a clinically diagnosed relative is not available for testing, the use of molecular genetic testing for determining the genetic status of at-risk relatives is problematic, and test results need to be interpreted with caution.

Failure to identify a disease-causing mutation in an at-risk family member does not eliminate the possibility that a PRKAR1A disease-causing mutation is present.

When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation.

Testing can be performed on an EDTA tube of blood, buccal swab and amniotic fluid.

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