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. 1998 Mar;62(3):610–619. doi: 10.1086/301766

Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling.

K C Sippel 1, R E Fraioli 1, G D Smith 1, M E Schalkoff 1, J Sutherland 1, B L Gallie 1, T P Dryja 1
PMCID: PMC1376960  PMID: 9497263

Abstract

Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 ( approximately 10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.

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Selected References

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  1. Bader J. L., Meadows A. T., Zimmerman L. E., Rorke L. B., Voute P. A., Champion L. A., Miller R. W. Bilateral retinoblastoma with ectopic intracranial retinoblastoma: trilateral retinoblastoma. Cancer Genet Cytogenet. 1982 Mar;5(3):203–213. doi: 10.1016/0165-4608(82)90026-7. [DOI] [PubMed] [Google Scholar]
  2. Bakker E., Van Broeckhoven C., Bonten E. J., van de Vooren M. J., Veenema H., Van Hul W., Van Ommen G. J., Vandenberghe A., Pearson P. L. Germline mosaicism and Duchenne muscular dystrophy mutations. Nature. 1987 Oct 8;329(6139):554–556. doi: 10.1038/329554a0. [DOI] [PubMed] [Google Scholar]
  3. Bakker E., Veenema H., Den Dunnen J. T., van Broeckhoven C., Grootscholten P. M., Bonten E. J., van Ommen G. J., Pearson P. L. Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations. J Med Genet. 1989 Sep;26(9):553–559. doi: 10.1136/jmg.26.9.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blanquet V., Turleau C., Gross-Morand M. S., Sénamaud-Beaufort C., Doz F., Besmond C. Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma. Hum Mol Genet. 1995 Mar;4(3):383–388. doi: 10.1093/hmg/4.3.383. [DOI] [PubMed] [Google Scholar]
  5. Bookstein R., Lee E. Y., To H., Young L. J., Sery T. W., Hayes R. C., Friedmann T., Lee W. H. Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2210–2214. doi: 10.1073/pnas.85.7.2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bourn D., Carter S. A., Evans D. G., Goodship J., Coakham H., Strachan T. A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals. Am J Hum Genet. 1994 Jul;55(1):69–73. [PMC free article] [PubMed] [Google Scholar]
  7. Bremner R., Du D. C., Connolly-Wilson M. J., Bridge P., Ahmad K. F., Mostachfi H., Rushlow D., Dunn J. M., Gallie B. L. Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma. Am J Hum Genet. 1997 Sep;61(3):556–570. doi: 10.1086/515499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Briard-Guillemot M. L., Bonaïti-Pellié C., Feingold J., Frézal J. Etude génétique du rétinoblastome. Humangenetik. 1974;24(4):271–284. doi: 10.1007/BF00297591. [DOI] [PubMed] [Google Scholar]
  9. Carlson E. A., Desnick R. J. Mutational mosaicism and genetic counseling in retinoblastoma. Am J Med Genet. 1979;4(4):365–381. doi: 10.1002/ajmg.1320040408. [DOI] [PubMed] [Google Scholar]
  10. Cavenee W. K., Dryja T. P., Phillips R. A., Benedict W. F., Godbout R., Gallie B. L., Murphree A. L., Strong L. C., White R. L. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. 1983 Oct 27-Nov 2Nature. 305(5937):779–784. doi: 10.1038/305779a0. [DOI] [PubMed] [Google Scholar]
  11. Colman S. D., Rasmussen S. A., Ho V. T., Abernathy C. R., Wallace M. R. Somatic mosaicism in a patient with neurofibromatosis type 1. Am J Hum Genet. 1996 Mar;58(3):484–490. [PMC free article] [PubMed] [Google Scholar]
  12. Cowell J. K., Bia B., Akoulitchev A. A novel mutation in the promotor region in a family with a mild form of retinoblastoma indicates the location of a new regulatory domain for the RB1 gene. Oncogene. 1996 Jan 18;12(2):431–436. [PubMed] [Google Scholar]
  13. Dryja T. P., Cavenee W., White R., Rapaport J. M., Petersen R., Albert D. M., Bruns G. A. Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med. 1984 Mar 1;310(9):550–553. doi: 10.1056/NEJM198403013100902. [DOI] [PubMed] [Google Scholar]
  14. Dryja T. P., Morrow J. F., Rapaport J. M. Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene. Hum Genet. 1997 Sep;100(3-4):446–449. doi: 10.1007/s004390050531. [DOI] [PubMed] [Google Scholar]
  15. Dryja T. P., Rapaport J., McGee T. L., Nork T. M., Schwartz T. L. Molecular etiology of low-penetrance retinoblastoma in two pedigrees. Am J Hum Genet. 1993 Jun;52(6):1122–1128. [PMC free article] [PubMed] [Google Scholar]
  16. Dunn J. M., Phillips R. A., Zhu X., Becker A., Gallie B. L. Mutations in the RB1 gene and their effects on transcription. Mol Cell Biol. 1989 Nov;9(11):4596–4604. doi: 10.1128/mcb.9.11.4596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
  18. Godbout R., Dryja T. P., Squire J., Gallie B. L., Phillips R. A. Somatic inactivation of genes on chromosome 13 is a common event in retinoblastoma. Nature. 1983 Aug 4;304(5925):451–453. doi: 10.1038/304451a0. [DOI] [PubMed] [Google Scholar]
  19. Greger V., Debus N., Lohmann D., Höpping W., Passarge E., Horsthemke B. Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet. 1994 Nov;94(5):491–496. doi: 10.1007/BF00211013. [DOI] [PubMed] [Google Scholar]
  20. Greger V., Passarge E., Horsthemke B. Somatic mosaicism in a patient with bilateral retinoblastoma. Am J Hum Genet. 1990 Jun;46(6):1187–1193. [PMC free article] [PubMed] [Google Scholar]
  21. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  22. Hogg A., Onadim Z., Baird P. N., Cowell J. K. Detection of heterozygous mutations in the RB1 gene in retinoblastoma patients using single-strand conformation polymorphism analysis and polymerase chain reaction sequencing. Oncogene. 1992 Jul;7(7):1445–1451. [PubMed] [Google Scholar]
  23. Kato M. V., Ishizaki K., Ejima Y., Kaneko A., Tanooka H., Sasaki M. S. Loss of heterozygosity on chromosome 13 and its association with delayed growth of retinoblastoma. Int J Cancer. 1993 Jul 30;54(6):922–926. doi: 10.1002/ijc.2910540609. [DOI] [PubMed] [Google Scholar]
  24. Kratzke R. A., Otterson G. A., Hogg A., Coxon A. B., Geradts J., Cowell J. K., Kaye F. J. Partial inactivation of the RB product in a family with incomplete penetrance of familial retinoblastoma and benign retinal tumors. Oncogene. 1994 May;9(5):1321–1326. [PubMed] [Google Scholar]
  25. Lohmann D. R., Brandt B., Höpping W., Passarge E., Horsthemke B. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet. 1994 Oct;94(4):349–354. doi: 10.1007/BF00201591. [DOI] [PubMed] [Google Scholar]
  26. Lohmann D. R., Gerick M., Brandt B., Oelschläger U., Lorenz B., Passarge E., Horsthemke B. Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet. 1997 Aug;61(2):282–294. doi: 10.1086/514845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lázaro C., Ravella A., Gaona A., Volpini V., Estivill X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med. 1994 Nov 24;331(21):1403–1407. doi: 10.1056/NEJM199411243312102. [DOI] [PubMed] [Google Scholar]
  28. McClure R. D., Nunes L., Tom R. Semen manipulation: improved sperm recovery and function with a two-layer Percoll gradient. Fertil Steril. 1989 May;51(5):874–877. doi: 10.1016/s0015-0282(16)60683-0. [DOI] [PubMed] [Google Scholar]
  29. McGee T. L., Cowley G. S., Yandell D. W., Dryja T. P. Detection of the XbaI RFLP within the retinoblastoma locus by PCR. Nucleic Acids Res. 1990 Jan 11;18(1):207–207. doi: 10.1093/nar/18.1.207-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Motegi T., Minoda K. A decreasing tendency for cytogenetic abnormality in peripheral lymphocytes of retinoblastoma patients with 13q14 deletion mosaicism. Hum Genet. 1984;66(2-3):186–189. doi: 10.1007/BF00286598. [DOI] [PubMed] [Google Scholar]
  31. Munier F., Pescia G., Jotterand-Bellomo M., Balmer A., Gailloud C., Thonney F. Constitutional karyotype in retinoblastoma. Case report and review of literature. Ophthalmic Paediatr Genet. 1989 Jun;10(2):129–150. doi: 10.3109/13816818909088353. [DOI] [PubMed] [Google Scholar]
  32. Noorani H. Z., Khan H. N., Gallie B. L., Detsky A. S. Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet. 1996 Aug;59(2):301–307. [PMC free article] [PubMed] [Google Scholar]
  33. Ohtani-Fujita N., Dryja T. P., Rapaport J. M., Fujita T., Matsumura S., Ozasa K., Watanabe Y., Hayashi K., Maeda K., Kinoshita S. Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. Cancer Genet Cytogenet. 1997 Oct 1;98(1):43–49. doi: 10.1016/s0165-4608(96)00395-0. [DOI] [PubMed] [Google Scholar]
  34. Ohtani-Fujita N., Fujita T., Aoike A., Osifchin N. E., Robbins P. D., Sakai T. CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene. 1993 Apr;8(4):1063–1067. [PubMed] [Google Scholar]
  35. Onadim Z., Hogg A., Baird P. N., Cowell J. K. Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6177–6181. doi: 10.1073/pnas.89.13.6177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ord T., Patrizio P., Marello E., Balmaceda J. P., Asch R. H. Mini-Percoll: a new method of semen preparation for IVF in severe male factor infertility. Hum Reprod. 1990 Nov;5(8):987–989. doi: 10.1093/oxfordjournals.humrep.a137233. [DOI] [PubMed] [Google Scholar]
  37. Orye E., Benoit Y., Coppieters R., Jeannin P., Vercruysse C., Delaey J., Delbeke M. J. A case of retinoblastoma, associated with histiocytosis-X and mosaicism of a deleted D-group chromosome (13q14 leads to q31). Clin Genet. 1982 Jul;22(1):37–39. [PubMed] [Google Scholar]
  38. Paller A. S., Syder A. J., Chan Y. M., Yu Q. C., Hutton E., Tadini G., Fuchs E. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med. 1994 Nov 24;331(21):1408–1415. doi: 10.1056/NEJM199411243312103. [DOI] [PubMed] [Google Scholar]
  39. Passos-Bueno M. R., Lima M. A., Zatz M. Estimate of germinal mosaicism in Duchenne muscular dystrophy. J Med Genet. 1990 Nov;27(11):727–728. doi: 10.1136/jmg.27.11.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ribeiro M. C., Andrade J. A., Erwenne C. M., Brunoni D. Bilateral retinoblastoma associated with 13q-mosaicism. Possible manifestation of a germinal mutation. Cancer Genet Cytogenet. 1988 Jun;32(2):169–175. doi: 10.1016/0165-4608(88)90279-8. [DOI] [PubMed] [Google Scholar]
  41. Rothberg P. G., Ponnuru S., Baker D., Bradley J. F., Freeman A. I., Cibis G. W., Harris D. J., Heruth D. P. A deletion polymorphism due to Alu-Alu recombination in intron 2 of the retinoblastoma gene: association with human gliomas. Mol Carcinog. 1997 Jun;19(2):69–73. doi: 10.1002/(sici)1098-2744(199707)19:2<69::aid-mc1>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  42. Sakai T., Ohtani N., McGee T. L., Robbins P. D., Dryja T. P. Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene. Nature. 1991 Sep 5;353(6339):83–86. doi: 10.1038/353083a0. [DOI] [PubMed] [Google Scholar]
  43. Sakai T., Toguchida J., Ohtani N., Yandell D. W., Rapaport J. M., Dryja T. P. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet. 1991 May;48(5):880–888. [PMC free article] [PubMed] [Google Scholar]
  44. Schappert-Kimmijser J., Hemmes G. D., Nijland R. The heredity of retinoblastoma. Ophthalmologica. 1966;151(2):197–213. doi: 10.1159/000304891. [DOI] [PubMed] [Google Scholar]
  45. Scheffer H., te Meerman G. J., Kruize Y. C., van den Berg A. H., Penninga D. P., Tan K. E., der Kinderen D. J., Buys C. H. Linkage analysis of families with hereditary retinoblastoma: nonpenetrance of mutation, revealed by combined use of markers within and flanking the RB1 gene. Am J Hum Genet. 1989 Aug;45(2):252–260. [PMC free article] [PubMed] [Google Scholar]
  46. Schubert E. L., Strong L. C., Hansen M. F. A splicing mutation in RB1 in low penetrance retinoblastoma. Hum Genet. 1997 Oct;100(5-6):557–563. doi: 10.1007/s004390050551. [DOI] [PubMed] [Google Scholar]
  47. Shimizu T., Toguchida J., Kato M. V., Kaneko A., Ishizaki K., Sasaki M. S. Detection of mutations of the RB1 gene in retinoblastoma patients by using exon-by-exon PCR-SSCP analysis. Am J Hum Genet. 1994 May;54(5):793–800. [PMC free article] [PubMed] [Google Scholar]
  48. Squire J., Dryja T. P., Dunn J., Goddard A., Hofmann T., Musarella M., Willard H. F., Becker A. J., Gallie B. L., Phillips R. A. Cloning of the esterase D gene: a polymorphic gene probe closely linked to the retinoblastoma locus on chromosome 13. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6573–6577. doi: 10.1073/pnas.83.17.6573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sterner J. M., Tao Y., Kennett S. B., Kim H. G., Horowitz J. M. The amino terminus of the retinoblastoma (Rb) protein associates with a cyclin-dependent kinase-like kinase via Rb amino acids required for growth suppression. Cell Growth Differ. 1996 Jan;7(1):53–64. [PubMed] [Google Scholar]
  50. Toguchida J., McGee T. L., Paterson J. C., Eagle J. R., Tucker S., Yandell D. W., Dryja T. P. Complete genomic sequence of the human retinoblastoma susceptibility gene. Genomics. 1993 Sep;17(3):535–543. doi: 10.1006/geno.1993.1368. [DOI] [PubMed] [Google Scholar]
  51. Vaughn G. L., Toguchida J., McGee T. L., Dryja T. P. PCR detection of the Tth 111 I RFLP at the RB locus. Nucleic Acids Res. 1990 Aug 25;18(16):4965–4965. doi: 10.1093/nar/18.16.4965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Vogel F. Genetics of retinoblastoma. Hum Genet. 1979 Nov 1;52(1):1–54. doi: 10.1007/BF00284597. [DOI] [PubMed] [Google Scholar]
  53. Vogel F., Rathenberg R. Spontaneous mutation in man. Adv Hum Genet. 1975;5:223–318. doi: 10.1007/978-1-4615-9068-2_4. [DOI] [PubMed] [Google Scholar]
  54. Wiggs J. L., Dryja T. P. Predicting the risk of hereditary retinoblastoma. Am J Ophthalmol. 1988 Sep 15;106(3):346–351. doi: 10.1016/0002-9394(88)90373-x. [DOI] [PubMed] [Google Scholar]
  55. Wiggs J., Nordenskjöld M., Yandell D., Rapaport J., Grondin V., Janson M., Werelius B., Petersen R., Craft A., Riedel K. Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med. 1988 Jan 21;318(3):151–157. doi: 10.1056/NEJM198801213180305. [DOI] [PubMed] [Google Scholar]
  56. Wijsman E. M. Recurrence risk of a new dominant mutation in children of unaffected parents. Am J Hum Genet. 1991 Apr;48(4):654–661. [PMC free article] [PubMed] [Google Scholar]
  57. Yandell D. W., Campbell T. A., Dayton S. H., Petersen R., Walton D., Little J. B., McConkie-Rosell A., Buckley E. G., Dryja T. P. Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med. 1989 Dec 21;321(25):1689–1695. doi: 10.1056/NEJM198912213212501. [DOI] [PubMed] [Google Scholar]
  58. Yandell D. W., Dryja T. P. Detection of DNA sequence polymorphisms by enzymatic amplification and direct genomic sequencing. Am J Hum Genet. 1989 Oct;45(4):547–555. [PMC free article] [PubMed] [Google Scholar]

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