Key result
Large 17q24.2-q24.3 deletions including the PRKAR1A gene were detected in 21.6% (11 of 51) of tested patients with Carney complex, correlating with severe and unusual phenotypes.
Cohort (n=51)
Yes
Array-based studies can detect PRKAR1A haploinsufficiency due to genomic deletions in over 20% of Carney complex patients who test negative by standard sequencing, often correlating with severe phenotypes.
Answers are grounded in this paper and cite their sources.
May support deletion testing in sequencing-negative Carney complex; hypothesis-generating for severe phenotypes and requires validation.
BACKGROUND: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC. SETTING: A tertiary care referral center was the setting for analysis of an international cohort of patients with CNC. METHODS: Methods included genome-wide array analysis followed by fluorescent in situ hybridization, mRNA, and other studies as well as a retrospective analysis of clinical information and phenotype-genotype correlation. RESULTS: We detected 17q24.2-q24.3 deletions of varying size that included the PRKAR1A gene in 11 CNC patients (of 51 tested). Quantitative PCR showed that these patients had significantly lower PRKAR1A mRNA levels. Phenotype varied but was generally severe and included manifestations that are not commonly associated with CNC, presumably due to haploinsufficiency of other genes in addition to PRKAR1A. CONCLUSIONS: A significant number (21.6%) of patients with CNC that are negative in currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing. Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and severe phenotypes who are PRKAR1A mutation-negative.
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Horvath et al. (2013) conducted a cohort in Carney complex (CNC) (n=51). 17q24.2-q24.3 deletions including the PRKAR1A gene was evaluated on Detection of 17q24.2-q24.3 deletions. Large 17q24.2-q24.3 deletions including the PRKAR1A gene were detected in 21.6% (11 of 51) of tested patients with Carney complex, correlating with severe and unusual phenotypes.
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