Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory.
OBJECTIVE
This study determines which clinical features predict positive test results among samples submitted for DNA-based diagnostic nevoid basal cell carcinoma syndrome (NBCCS) testing, and further defines the mutational spectrum of the PTCH gene.


METHODS
DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction products from exons 1 to 23 of the PTCH gene were directly sequenced. Pedigree phenotypic information was obtained by written questionnaire.


RESULTS
Among 106 presumably unrelated pedigrees, 44 independent mutations were found in 47 families. There were 11 nonsense mutations; 1 in-frame deletion; 17 deletions, 6 insertions, and 1 deletion-insertion that generated frameshifts; 5 splice-site mutations; 1 in-frame duplication; and 2 presumptive missense mutations. Twenty-seven of 46 pedigrees (58.7%) with two or more typical radiographic or pathologic features of NBCCS tested positive for PTCH mutations. Of these, 26 had jaw cysts in combination with other characteristics or neoplasms including basal cell carcinomas, palmar pits, skeletal abnormalities, ocular abnormalities, medulloblastomas, cardiac or ovarian fibromas, calcification of the falx cerebri, polydactyly, cleft lip and/or palate, and agenesis of the corpus callosum or other central nervous system malformations. None of the 13 pedigrees solely affected by multiple or early-onset basal cell carcinomas and none of the four pedigrees with jaw cysts alone had PTCH mutations.


CONCLUSIONS
Pedigrees with multiple features of NBCCS were most likely to test positive for PTCH mutations. Pedigrees with multiple or early-onset basal cell carcinomas without other features of the disease did not test positive for PTCH mutations.
Klein
Roger D
RD
DNA Diagnostic Laboratory, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Dykas
Daniel J
DJ
Bale
Allen E
AE
D000293:Adolescent; D000328:Adult; D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005820:Genetic Testing / Q000706:statistics & numerical data*; D006801:Humans; D008875:Middle Aged; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010375:Pedigree; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA
D017931:DNA Primers; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface