R. Shimkets et al., MOLECULAR ANALYSIS OF CHROMOSOME 9Q DELETIONS IN 2 GORLIN SYNDROME PATIENTS, American journal of human genetics, 59(2), 1996, pp. 417-422
Gorlin syndrome is an autosomal dominant disorder characterized by mul
tiple basal cell carcinomas, medulloblastomas, ovarian fibromas, and a
variety of developmental defects. All affected individuals share cert
ain key features, but there is significant phenotypic variability with
in and among kindreds with respect to malformations. The gene (NBCCS)
maps to chromosome 9q22, and allelic loss at this location is common i
n tumors from Gorlin syndrome patients. Two recessive cancer-predispos
ition syndromes, xeroderma pigmentosum group A (XPAC) and Fanconi anem
ia group C (FACC), map to the NBCCS region; and unusual, dominant muta
tions in these genes have been proposed as the cause of Gorlin syndrom
e. This study presents cytogenetic and molecular characterization of g
erm-line deletions in one patient with a chromosome 9q22 deletion and
in a second patient with a deletion of 9q22-q31. Both have typical fea
tures of Gorlin syndrome plus additional findings, including mental re
tardation, conductive hearing loss, and failure to thrive. That Gorlin
syndrome can be caused by null mutations (deletions) rather than by a
ctivating mutations has several implications. First, in conjunction wi
th previous analyses of allelic loss in tumors, this study provides ev
idence that associated neoplasms arise with homozygous inactivation of
the gene. In addition, dominant mutations of the XPAC and FACC1 genes
can be ruled out as the cause of Gorlin syndrome, since the two patie
nts described have null mutations. Finally, phenotypic features that s
how variable expression must be influenced by genetic background, epig
enetic effects, somatic mutations, or environmental factors, since the
se two patients with identical alterations (deletions) of the Gorlin s
yndrome gene have somewhat different manifestations of Gorlin syndrome
.