Graziano Pescia

Paternal selection favoring mutant alleles of the retinoblastoma susceptibility gene

SummaryPenetrance and segregation rates of mutant Rb-1 alleles were assessed in all 51 members of eight kindreds with hereditary retinoblastoma by concomitant ophthalmologic examination and determination of seven intragenic restriction fragment length polymorphisms (RFLPs). Penetrance was in the range reported in the literature except for one family in which it was only 42.8%. However, the odds of transmitting a mutant Rb-1 allele from one generation to the next were 25∶9 in this population, much above the Mendelian 1∶1 ratio (P < 0.025). This preferential transmission was discovered through the use of molecular information. Further analysis revealed that this distortion was due to preferential inheritance among children of male carriers (18∶4, P < 0.005). No difference from a 1∶1 segregation ratio could be detected among the children of female carriers (7∶5). These findings were consistent with a review of relevant data in the literature.

Evidence of Somatic and Germinal Mosaicism in Pseudo–Low-Penetrant Hereditary Retinoblastoma, by Constitutional and Single-Sperm Mutation Analysis

This study was supported by the Ligue Suisse contre le Cancer (grant SKL 443-2-1997) and the Recherche Suisse contre le Cancer (grant AKT 621). We thank Dr. Phil Shaw for his discussions.

Constitutional Karyotype in Retinoblastoma Case Report and Review of Literature

High resolution karyotype was performed in 13 retinoblastoma patients. A mosaic pattern for del(13)(q14.1;q14.3) was found in a girl with sporadic bilateral retinoblastoma and midface dysmorphism. In addition, 162 cases of 13q aberrations were reviewed, including 140 retinoblastoma patients and 22 non-penetrance 13q14 deletions. Some epidemiological and genetic involvements are discussed.

Delineation of a 1-cM region on distal 5q containing the locus for corneal dystrophies Groenouw type I and lattice type I and exclusion of the candidate genes SPARC and LOX.

Granular Groenouw type I (CDGG1) and lattice type I (CDL1) corneal dystrophies are two distinct potentially blinding conditions. These two entities were recently mapped to a region on chromosome 5q. We have investigated 2 families of Swiss origin with CDGG1 and CDL1 by linkage analysis. Our data show a maximum lod score of 5.38 at θ = 0.00 for marker D5S393 in CDL1 and 4.17 at θ = 0.00 for D5S658 in CDGG1. When combined, these families show a maximum lod score of 9.22 for D5S393 at θ = 0.00. This confirms previous reports. Furthermore, we describe a recombination centromeric to D5S399 in a member of the CDL1 family. Haplotype analysis in the 4 branches of the CDGG1 family demonstrated a common chromosomal region including D5S393 and D5S399 in all the affected members. By combining our data with previously reported mapping information and assuming that CDGG1 and CDL1 are allelic manifestations of the same gene, we can refine the location of the CDGG1/CDL1 gene to a 1-cM region on chromosome 5q. Using candidate genes in the 5q22-q32 interval, we investigated the possibility that mutations in the SPARC or LOX genes cause these corneal diseases. Several recombinations occurred between these two genes and CDGG1/CDL1 in our 2 families, thus excluding this hypothesis.

Prognostic factors associated with loss of heterozygosity at the RB1 locus in retinoblastoma

The nature of the tumorigenic mutation was analyzed in 30 retinoblastoma (Rb) tumors (16 non-hereditary and 14 hereditary) and categorized into loss of heterozygosity (LOH) or retention of heterozygosity (non-LOH) at the RB1 locus. These genotypic characteristics were compared with the clinicopathological phenotype for possible correlation. The overall frequency of LOH was roughly 55%, in both hereditary and non-hereditary Rb. The presence of LOH was preferentially associated with differentiated tumors and absence of choroidal invasion. LOH was found in 82% of females versus 33% of males. Finally, LOH-initiated tumors were associated with a significantly younger age at diagnosis in hereditary Rb. In conclusion, the preferential association of LOH with absence of choroidal invasion, tumoral differentiation, and younger age at diagnosis may establish LOH as a prognostic marker in Rb patients.

A "new" allele of esterase D in a retinoblastoma family.

SummaryWe describe a new rare allele for esterase D (EsD) occurring in a Portuguese family with retinoblastoma in two generations.

Applications cliniques du diagnostic moléculaire du rétinoblastome dans 15 families

Purpose In 40% retinoblastoma (Rb) results from a hereditary mutation of the Rb susceptibility gene (RB1). In this study, we tested the usefulness of intragenic DNA analysis for ophthalmologic follow-up in affected families. Methods Molecular analysis was performed on 103 DNA samples of 15 Rb families. We used 7 intragenic polymorphic markers and one within the ESD gene for mutation linkage analysis. Findings DNA analysis was informative in 88% of relatives at risk of developing Rb. Among them, the presence of a mutated RB1 allele was excluded in 46%, while 29% were unaffected carriers and 25% had inherited the Rb predisposition. Conclusion In the majority of familial Rb, the DNA analysis allows the identification of children carrying a RB1 mutation and who will need a close ophthalmologic follow-up under general anesthesia. When the mutated gene is absent, ophthalmological examination under narcosis is unnecessary. Finally, identification of asymptomatic carriers improve the accuracy of genetic counselling.