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November 1993

Pseudo Low Penetrance in Retinoblastoma: Fortuitous Familial Aggregation of Sporadic Cases Caused by Independently Derived Mutations in Two Large Pedigrees

Author Affiliations

From the Division of Ophthalmology, Childrens Hospital of Los Angeles (Calif) and the University of Southern California School of Medicine (Drs Munier and Murphree); the Laboratory of Oncology Research, Research Division, Wills Eye Hospital, Philadelphia, Pa (Drs Wang and Donoso); the Division of Human Genetics, Department of Pediatrics, University of California, Irvine Medical Center (Dr Spence); Division Autonome de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (Drs Thonney and Pescia); and Hôpital Jules Gonin, Département d'Ophtalmolgie, Faculté de Médecine de l'Université de Lausanne (Dr Balmer).

Arch Ophthalmol. 1993;111(11):1507-1511. doi:10.1001/archopht.1993.01090110073028

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 germline 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.