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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1989 Aug;45(2):252–260.

Linkage analysis of families with hereditary retinoblastoma: nonpenetrance of mutation, revealed by combined use of markers within and flanking the RB1 gene.

H Scheffer 1, G J te Meerman 1, Y C Kruize 1, A H van den Berg 1, D P Penninga 1, K E Tan 1, D J der Kinderen 1, C H Buys 1
PMCID: PMC1683338  PMID: 2569269

Abstract

Nonpenetrance of the inherited mutation responsible for retinoblastoma has been reported. By DNA analysis in families with hereditary retinoblastoma, it is possible to identify healthy individuals in whom the mutation is nonpenetrant. This requires the use of DNA markers both within and flanking the retinoblastoma gene. We have analyzed the segregation of several markers in 19 families (69 meioses) with hereditary retinoblastoma. In two families a carrier was identified who showed nonpenetrance of the mutation predisposing to retinoblastoma. The intragenic markers were informative in 15 pedigrees. The use of flanking markers from the same chromosomal region caused an increase of the number of informative families to 18. No crossing-over within the gene was observed. In one family an inherited deletion involving one of the RB1 alleles was detected. Our findings emphasize the use of a combination of both intragenic and flanking markers to obtain both the highest reliability of carrier detection in families with hereditary retinoblastoma and an accurate estimate of the frequency of nonpenetrance.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bowcock A. M., Farrer L. A., Hebert J. M., Agger M., Sternlieb I., Scheinberg I. H., Buys C. H., Scheffer H., Frydman M., Chajek-Saul T. Eight closely linked loci place the Wilson disease locus within 13q14-q21. Am J Hum Genet. 1988 Nov;43(5):664–674. [PMC free article] [PubMed] [Google Scholar]
  2. Carritt B., Welch H. M., Parry-Jones N. J. Sequences homologous to the human D1S1 locus present on human chromosome 3. Am J Hum Genet. 1986 Apr;38(4):428–436. [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Cavenee W., Leach R., Mohandas T., Pearson P., White R. Isolation and regional localization of DNA segments revealing polymorphic loci from human chromosome 13. Am J Hum Genet. 1984 Jan;36(1):10–24. [PMC free article] [PubMed] [Google Scholar]
  5. Chaum E., Ellsworth R. M., Abramson D. H., Haik B. G., Kitchin F. D., Chaganti R. S. Cytogenetic analysis of retinoblastoma: evidence for multifocal origin and in vivo gene amplification. Cytogenet Cell Genet. 1984;38(2):82–91. doi: 10.1159/000132037. [DOI] [PubMed] [Google Scholar]
  6. Chu G., Vollrath D., Davis R. W. Separation of large DNA molecules by contour-clamped homogeneous electric fields. Science. 1986 Dec 19;234(4783):1582–1585. doi: 10.1126/science.3538420. [DOI] [PubMed] [Google Scholar]
  7. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Connolly M. J., Payne R. H., Johnson G., Gallie B. L., Allderdice P. W., Marshall W. H., Lawton R. D. Familial, EsD-linked, retinoblastoma with reduced penetrance and variable expressivity. Hum Genet. 1983;65(2):122–124. doi: 10.1007/BF00286647. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Dunn J. M., Phillips R. A., Becker A. J., Gallie B. L. Identification of germline and somatic mutations affecting the retinoblastoma gene. Science. 1988 Sep 30;241(4874):1797–1800. doi: 10.1126/science.3175621. [DOI] [PubMed] [Google Scholar]
  11. Ellsworth R. M. The practical management of retinoblastoma. Trans Am Ophthalmol Soc. 1969;67:462–534. [PMC free article] [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Fung Y. K., Murphree A. L., T'Ang A., Qian J., Hinrichs S. H., Benedict W. F. Structural evidence for the authenticity of the human retinoblastoma gene. Science. 1987 Jun 26;236(4809):1657–1661. doi: 10.1126/science.2885916. [DOI] [PubMed] [Google Scholar]
  15. Gallie B. L., Ellsworth R. M., Abramson D. H., Phillips R. A. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer. 1982 Apr;45(4):513–521. doi: 10.1038/bjc.1982.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Horsthemke B., Barnert H. J., Greger V., Passarge E., Höpping W. Early diagnosis in hereditary retinoblastoma by detection of molecular deletions at gene locus. Lancet. 1987 Feb 28;1(8531):511–512. doi: 10.1016/s0140-6736(87)92125-8. [DOI] [PubMed] [Google Scholar]
  17. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lalande M., Dryja T. P., Schreck R. R., Shipley J., Flint A., Latt S. A. Isolation of human chromosome 13-specific DNA sequences cloned from flow sorted chromosomes and potentially linked to the retinoblastoma locus. Cancer Genet Cytogenet. 1984 Dec;13(4):283–295. doi: 10.1016/0165-4608(84)90073-6. [DOI] [PubMed] [Google Scholar]
  19. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  20. Lee W. H., Bookstein R., Hong F., Young L. J., Shew J. Y., Lee E. Y. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987 Mar 13;235(4794):1394–1399. doi: 10.1126/science.3823889. [DOI] [PubMed] [Google Scholar]
  21. Matsunaga E. Hereditary retinoblastoma: penetrance, expressivity and age of onset. Hum Genet. 1976 Jul 7;33(1):1–15. doi: 10.1007/BF00447281. [DOI] [PubMed] [Google Scholar]
  22. Mitchell C. D., Cowell J. K. Molecular evidence that the esterase-D gene lies proximal to the retinoblastoma susceptibility locus in chromosome region 13q14. Hum Genet. 1988 Dec;81(1):57–60. doi: 10.1007/BF00283730. [DOI] [PubMed] [Google Scholar]
  23. Scheffer H., Penninga D., Goor N., Pearson P. L., Buys C. H. An anonymous single copy genomic clone at 13q12-13q13 identifies three RFLPs [HGM8 assignment no. D13S11]. Nucleic Acids Res. 1986 Apr 11;14(7):3148–3148. doi: 10.1093/nar/14.7.3148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Scheffer H., van der Lelie D., Aanstoot G. H., Goor N., Nienhaus A. J., van der Hout A. H., Pearson P. L., Buys C. H. A straightforward approach to isolate DNA sequences with potential linkage to the retinoblastoma locus. Hum Genet. 1986 Nov;74(3):249–255. doi: 10.1007/BF00282543. [DOI] [PubMed] [Google Scholar]
  25. Sparkes R. S., Sparkes M. C., Wilson M. G., Towner J. W., Benedict W., Murphree A. L., Yunis J. J. Regional assignment of genes for human esterase D and retinoblastoma to chromosome band 13q14. Science. 1980 May 30;208(4447):1042–1044. doi: 10.1126/science.7375916. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Turleau C., de Grouchy J., Chavin-Colin F., Junien C., Séger J., Schlienger P., Leblanc A., Haye C. Cytogenetic forms of retinoblastoma: their incidence in a survey of 66 patients. Cancer Genet Cytogenet. 1985 Apr 15;16(4):321–334. doi: 10.1016/0165-4608(85)90240-7. [DOI] [PubMed] [Google Scholar]
  28. Vogel F. Genetics of retinoblastoma. Hum Genet. 1979 Nov 1;52(1):1–54. doi: 10.1007/BF00284597. [DOI] [PubMed] [Google Scholar]
  29. 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]

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