Pseudo low penetrance in retinoblastoma. Fortuitous familial aggregation of sporadic cases caused by independently derived mutations in two large pedigrees
F. L. Munier, M. X. Wang, M. A. Spence, F. Thonney, A. Balmer, G. Pescia, L. A. Donoso and A. L. Murphree
Division of Ophthalmology, Childrens Hospital of Los Angeles, Calif.
OBJECTIVE: The disparate occurrence of few cases of retinoblastoma in the
same extended pedigree confronts us with the unsolved problem of a
low-penetrant autosomal-dominant trait vs fortuitous familial aggregation
of sporadic cases. Determination as to whether the disease arises from a
common inherited mutation or sporadic mutations has important implications
for genetic counseling. This is illustrated in this report of two presumed
low-penetrant retinoblastoma pedigrees characterized by two distantly
affected relatives connected through apparently healthy carriers. DESIGN:
We mathematically modeled the inheritance patterns and calculated the a
priori relative probabilities of heredity with low penetrance vs chance
occurrence of independent mutations for each pedigree. The derived odds
clearly show that the disease, which occurred twice in each family, most
likely resulted from unrelated mutations. To prove this, extensive DNA
testing was conducted, including determination of intragenic RB1 DNA
sequence polymorphisms and screening for mutation using the polymerase
chain reaction coupled with single-strand conformation polymorphism
analysis. PATIENTS: All living key members from both pedigrees were
included. RESULTS: Consistent with our initial expectation, there was no
common intragenic haplotype or common germ-line mutation that segregated
with the disease phenotype in either of these two families. CONCLUSIONS: We
therefore conclude that collateral incidence of retinoblastoma in these two
pedigrees occurred by chance and not according to autosomal-dominant
inheritance with low penetrance. Furthermore, our data provide the first
evidence, to our knowledge, that related individuals may have independent
mutations involving an identical gene locus, giving rise to an artefactual
inheritance pattern.
