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A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations
Author(s) -
Gennari Monia,
Stratakis Constantine A.,
Hovarth Anelia,
Pirazzoli Piero,
Cicognani Alessandro
Publication year - 2008
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2008.03286.x
Subject(s) - haploinsufficiency , carney complex , frameshift mutation , genetics , mutation , penetrance , biology , nonsense mutation , proband , context (archaeology) , genetic testing , phenotype , cancer research , gene , missense mutation , paleontology
Summary Context Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22–24. There is little phenotype–genotype correlation known to date. Objective To study the genotype–phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. Design The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. Patients The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. Results The PRKAR1A ‐inactivating mutation c.502 +1G > A in the intron 5 splice‐donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. Conclusions A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.