title: Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects.
abstract: BACKGROUND
  Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease.
  
  
  METHODS
  Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346.
  
  
  RESULTS
  In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease.
  
  
  CONCLUSIONS
  The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care.
authors.affiliation: Institute of Biology and Medical Genetics of the 1st Faculty of Medicine and General Teaching Hospital, Charles University, Albertov 4, Prague 2, 128 00, Czech Republic. Jitka.Stekrova@lf1.cuni.cz
authors.forename: Jitka
authors.initials: J
authors.lastname: Stekrova
authors.forename: Martina
authors.initials: M
authors.lastname: Sulova
authors.forename: Vera
authors.initials: V
authors.lastname: Kebrdlova
authors.forename: Katerina
authors.initials: K
authors.lastname: Zidkova
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kotlas
authors.forename: Denisa
authors.initials: D
authors.lastname: Ilencikova
authors.forename: Kamila
authors.initials: K
authors.lastname: Vesela
authors.forename: Milada
authors.initials: M
authors.lastname: Kohoutova
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D001483:Base Sequence; D018153:Czech Republic; D005091:Exons; D017353:Gene Deletion; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D018154:Slovakia