Novel APC promoter and exon 1B deletion and allelic silencing in three mutation-negative classic familial adenomatous polyposis families.
BACKGROUND
The overwhelming majority (approximately 80%) of individuals with classic familial adenomatous polyposis (FAP) exhibit mutations in the coding sequence of the adenomatous polyposis coli (APC) tumor suppressor gene. Families without detectable APC mutations are unable to benefit from the use of genetic testing for clinical management of this autosomal dominant syndrome.


METHODS
We used exome sequencing and linkage analysis, coupled with second-generation sequencing of the APC locus including non-coding regions to investigate three APC mutation-negative classical FAP families.


RESULTS
We identified a novel ~11 kb deletion localized 44 kb upstream of the transcription start site of APC that encompasses the APC 1B promoter and exon. This deletion was present only in affected family members of one kindred with classical FAP. Furthermore, this same deletion with identical breakpoints was found in the probands of two additional APC mutation-negative classical FAP kindreds. Phasing analysis of single nucleotide polymorphisms (SNPs) around the deletion site in the three probands showed evidence of a shared haplotype, suggesting a common founder deletion in the three kindreds. SNP analysis within the coding sequence of APC, revealed that this ~11 kb deletion was accompanied by silencing of one of the APC alleles in blood-derived RNA of affected individuals.


CONCLUSIONS
These results support the causal role of a novel promoter deletion in FAP and suggest that non-coding deletions, identifiable using second-generation sequencing methods, may account for a significant fraction of APC mutation-negative classical FAP families.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri USA.
Yiing
Y
Lin
Department of Cardiovascular Medicine, Stanford University, Palo Alto, California USA.
Shin
S
Lin
St. Francis Medical Center, Cape Girardeau, Missouri USA.
Melanie D
MD
Baxter
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri USA.
Lawrence
L
Lin
Division of Gastroenterology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8124, St. Louis, Missouri MO 63110 USA.
Susan M
SM
Kennedy
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri USA.
Zhengyan
Z
Zhang
College of Medicine, Ohio State University, Columbus, Ohio USA.
Paul J
PJ
Goodfellow
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri USA.
William C
WC
Chapman
Division of Gastroenterology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8124, St. Louis, Missouri MO 63110 USA.
Nicholas O
NO
Davidson