title: Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Section on Endocrinology and Genetics (P.S., E.L., F.R.F., I.L., E.G., M.F.K., C.L., C.A.S.), Program on Developmental Endocrinology and Genetics and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Department of Biochemistry and Molecular Medicine (A.H.), The George Washington University, Washington, D.C. 20037; Department of Molecular Medicine (A.V., A.F., O.Z.), University of Pavia, Pavia 27100, Italy; Division of Genetics and Endocrinology (A.D., I.A.H.), Boston Children's Hospital, Boston, Massachusetts; Regional Medical Genetics Center (P.J.M.), Queens University Belfast, Belfast BT9 7AB, United Kingdom; and Quest Diagnostics Nichols Institute (E.D.S., M.A.S., J.C.K., Z.D., P.M.), Chantilly, Virginia 20151.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Salpea
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Edra
authors.initials: E
authors.lastname: London
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.forename: Isaac
authors.initials: I
authors.lastname: Levy
authors.forename: Evgenia
authors.initials: E
authors.lastname: Gourgari
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Holm
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Keil
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.forename: Eric D
authors.initials: ED
authors.lastname: Smith
authors.forename: Marc A
authors.initials: MA
authors.lastname: Sanidad
authors.forename: JoAnn C
authors.initials: JC
authors.lastname: Kelly
authors.forename: Zunyan
authors.initials: Z
authors.lastname: Dai
authors.forename: Philip
authors.initials: P
authors.lastname: Mowrey
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000293:Adolescent; D000328:Adult; D056733:Carney Complex / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015331:Cohort Studies; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human