Kimberly C. Sippel, Rebecca E. Fraioli, Gary D. Smith, Mary E

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Frequency of Somatic and Germ-Line Mosaicism in Retinoblastoma: Implications for Genetic Counseling Kimberly C. Sippel, Rebecca E. Fraioli, Gary D. Smith, Mary E. Schalkoff, Joanne Sutherland, Brenda L. Gallie, Thaddeus P. Dryja The American Journal of Human Genetics Volume 62, Issue 3, Pages 610-619 (March 1998) DOI: 10.1086/301766 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of families with one member in whom mosaicism could be documented. The family identification number appears at the upper left of each pedigree. A blackened symbol indicates an individual affected with bilateral retinoblastoma; a half-blackened symbol indicates an individual affected with unilateral retinoblastoma. The letters below each individual indicate the haplotypes at the RB1 locus in leukocyte DNA; letters under the word “TUMOR” indicate the haplotypes that were found in tumor DNA. Alleles at intragenic polymorphisms were used to deduce haplotypes; in each family, the haplotypes were labeled alphabetically, beginning with those found in the father (unless the father was not analyzed). No haplotype letters appear below individuals who were not analyzed. An asterisk (*) or a small circle (°) indicates an allele with a mutation; the mutations to which these symbols refer are noted below each pedigree. The abbreviation “del” designates a deletion of the entire RB1 gene, as revealed by Southern blotting, unless otherwise indicated. A plus sign (+) (family 271) indicates a normal chromosome 13, determined by karyotyping; no DNA analysis was performed on these individuals. Each pedigree is described in the text. The American Journal of Human Genetics 1998 62, 610-619DOI: (10.1086/301766) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 SSCP analysis of the nonsense mutation Arg320End, in family 452. The results of analysis of leukocyte DNA from each individual appear directly below that person's symbol. Numerous bands are present because the amplified fragment was digested with an endonuclease before SSCP analysis. The mutant fragment is indicated with an arrow at the lower right. The intensity of the mutant fragment in the mother (blackened circle) is less than in her affected son (blackened square); this reduction in intensity was also observed in quantitative sequencing (data not shown). The American Journal of Human Genetics 1998 62, 610-619DOI: (10.1086/301766) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 SSCP analysis of the nonsense mutation Arg556End, in family 262. The results of analysis of blood (leukocyte) DNA from each individual are located directly below that person's symbol, except for the father (unblackened square, upper left), under whose symbol are lanes B and S, which show results from leukocyte and purified sperm DNA, respectively. The lanes under the terms “10%,” “5%,” and “2%” show results from mixtures of wild-type and mutant DNA (derived from the mother and the younger affected daughter, respectively) that would contain the indicated proportions of mutant and wild-type alleles. On the basis of these scaling lanes, we estimate the proportion of mutant sperm to be ∼5%. The American Journal of Human Genetics 1998 62, 610-619DOI: (10.1086/301766) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Analysis of the frameshift mutation Arg467(11-bp ins) in family 139. SSCP results of analysis of leukocyte DNA appear directly below the symbol for each individual, except for lanes under the father (unblackened square) and the affected son (blackened square), where B indicates leukocyte DNA; S, semen DNA; and T, tumor DNA. The affected son displays approximately equal amounts of mutant and normal DNA in blood and tumor. Unaffected family members display only the wild-type sequence, with the exception of the father, who displays the mutant band in both blood and semen, but at a reduced intensity. The lanes under the terms “40%,” “30%,” “20%,” and “10%” show results from mixtures of wild-type and mutant DNA (derived from the unaffected daughter's leukocytes and the affected son's tumor, respectively) that would contain the indicated proportions of mutant and wild-type alleles. On the basis of these lanes, we estimate the proportion of mutant sperm in the father's semen to be ∼20%–30%. The American Journal of Human Genetics 1998 62, 610-619DOI: (10.1086/301766) Copyright © 1998 The American Society of Human Genetics Terms and Conditions