Heterozygous tandem duplication within the PTCH1 gene results in nevoid basal cell carcinoma syndrome.
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. Using multiplex ligation-dependent probe amplification, we identified a heterozygous tandem duplication within the PTCH1 gene in a 14-year-old girl with typical NBCCS. We have sequenced the chromosomal breakpoint and determined the duplication as tandem in orientation and 18,814 bp in size. The fusion occurred between non-repetitive elements with an overlap of three nucleotides. The duplicated segment began at exon 10 and ended at intron 17. Subsequent analysis of cDNA from the patient showed the expression of mutant mRNA species containing a duplicated segment spanning exons 11-17, resulting in a frameshift and premature stop codon. This is the first reported case of NBCCS due to a tandem multiexon duplication of PTCH1 representing a novel mechanism leading to the NBCCS phenotype, and highlights the importance of copy number analysis as an adjunct to exon sequencing in identifying infrequent mutational events in PTCH1.
Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan.
Rika
R
Kosaki
Kazuaki
K
Nagao
Kohzoh
K
Kameyama
Maiko
M
Suzuki
Katsunori
K
Fujii
Toshiyuki
T
Miyashita
D000293:Adolescent; D000595:Amino Acid Sequence; D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D001483:Base Sequence; D005091:Exons; D005260:Female; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D014158:Transcription, Genetic
C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface