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Counselling under genetic heterogeneity: a practical approach
Steven Narod,
Corresponding Author
Steven Narod
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France
McGill University Division of Medical Genetics Royal Victoria Hospital 687 Pine Avenue Room H5–63 Montreal, Quebec H3A1A1 CanadaSearch for more papers by this authorSteven Narod,
Corresponding Author
Steven Narod
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France
McGill University Division of Medical Genetics Royal Victoria Hospital 687 Pine Avenue Room H5–63 Montreal, Quebec H3A1A1 CanadaSearch for more papers by this authorAbstract
Hereditary diseases due to mutation at different gene loci may be indistinguishable phenotypically. In these situations genetic risk predictions using polymorphic markers may be hampered if an individual family is not sufficiently informative to permit it to be assigned to one or the other linkage group. To provide the most useful estimates of risk, the probability of linkage to a particular chromosome region should be determined prior to calculating risk estimates using the marker system. The probability can be calculated directly using the lod score generated for the family. The individual carrier risk is then the average of the carrier risks determined for linkage to different genetic loci, weighted by the probability of linkage to each group. Several examples are provided.
References
- Bear, J. C., P. S. Parfrey, J. Morgan, B. C. Cramer, P. J. McManamon, M. H. Gault, D. N. Churchill, N. Singh, R. Hewitt, S. Somlo & S. Reeders (1989) Autosomal dominant polycystic kidney disease: untrasonographic detection and prognosis of PKD1 and PKD2 forms. Am. J. Hum. Genet. 45, A39.
- Bodmer, W. F., C. J. Bailey, J. Bodmer, H. J. R. Bussey, A. Ellis, P. Gorman, F. C. Lucibello, V. A. Murday, S. H. Rider, P. Scambler, D. Sheer, E. Solomon & N. K. Spurr (1987) Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature 328, 614–616.
- Brissenden, J. E., J. M. Roscoe & M. Silverman (1988) Linkage heterogeneity in autosomal dominant polycystic kidney disease. Am. J. Hum. Genet. 43, A78.
- Brzustowicz, L. M., T. Lehner, L. H. Castilla, G. K. Penchaszadeh, K. C. Wilhelmsen, R. Daniels, K. E. Davies, M. Leppert, F. Ziter, D. Wood, V. Dubowitz, K. Zerres, I. Hausmanowa-Petrusewicz, J. Ott, T. L. Musnat & T. C. Gilliam (1990) Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3. Nature 344, 540–541.
- Cavilli-Sforza, L. L. & M.-C. King (1986) Detecting linkage for genetically heterogenous diseases and detecting heterogeneity with linkage data. Am. J. Hum. Genet. 38, 599–616.
- Conboy, J., N. Mohandas, G. Tchernia & Y. W. Kan (1986) Molecular basis of hereditary elliptocytosis due to protein 4.1 deficiency. N. Engl. J. Med. 315, 680–685.
- Connor, J. M., L. A. Pirrit, J. R. W. Yates, A. E. Fryer & M. A. Ferguson-Smith (1987) Linkage of the tuberous sclerosis locus to a DNA polymorphism detected by v-abl. J. Med. Genet. 24, 544–546.
- Flodman, P., R. Baumann, K. Yoshiyama & M. Smith (1989) Classification of tuberous sclerosis families based on linkage analysis with 9q34 and 11q22–23 markers. Am. J. Hum. Genet. 45, A139.
- Fryer, A. E., A. Chalmers, J. M. Connor, I. Fraser, S. Povey, A. D. Yates, J. R. W. Yates & J. P. Osborne (1987) Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1, 659–661.
- Kandt, R. S., M. A. Pericak-Vance, W.-H. Hung, R. J. M. Gardner, M. Nellist, K. Phillips, K. Warner, N. Laing & A. D. Roses (1988) Multilocus linkage analysis in tuberous sclerosis. Am. J. Hum. Genet. 43, A148.
- Kimberling, W. J., P. R. Fain, J. B. Kenyon, D. Goldgar, E. Sujansky & P. Gabow (1988) Linkage heterogeneity of autosomal dominant polycystic kidney disease. N. Engl. J. Med. 319, 913–918.
- Lathrop, G. M., J.-M. Lalouel, C. Julier & J. Ott (1984) Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. (USA) 81, 3443–3446.
- Leppert, M., M. Dobbs, P. Scambler, P. O'Connell, Y. Nakamura, D. Stauffer, S. Woodward, R. Burt, J. Hughes, E. Gardner, M. Lathrop, J. Wasmuth, J.-M. Lalouel & R. White (1987) The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 238, 1411–1413.
- Leppert, M., R. Burt, J. P. Hughes, W. Samowitz, Y. Nakamra, S. Woodward, E. Gardner, J.-M. Lalouel & R. White (1990) Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N. Engl. J. Med. 322, 904–908.
- Melki, J., P. Abdelhak, P. Sheth, M. F. Bachelot, P. Purlet, A. Marcadet, J. Aicardi, A. Barois, J. P. Carriere, M. Fardeau, D. Fontan, G. Ponsot, T. Billete, C. Angelini, C. Barbosa, G. Ferriere, G. Lanzi, A. Ottolini, M. C. Babron, D. Cohen, A. Hanauer, F. Clerget-Darpoux, M. Lathrop, A. Munnich & J. Frezal (1990) Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature 344, 767–768.
- Morton, N. E. (1956) The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8, 80–96.
- Morton, N. E. J.-M. Lalouel, J. F. Jackson, R. D. Currier & S. Yee (1980) Linkage studies in spinocerebellar ataxia (SCA). Am. J. Med. Genet. 6, 251–257.
- Narod, S. A., H. Sobol, Y. Nakamura, C. Calmettes, J.-L. Baulieu, J.-C. Bigorne, G. Chabrier, J. Couette, J.-L. de Gennes, J. Duprey, P. Gardet, P.-J. Guillausseau, D. Guilloteau, C. Houdent, J. Lefebvre, E. Modigliani, C. Parmentier, M. Pugeat, C. Siame, J. Tourniare, J.-C. Vandroux, J.-M. Vinot & G. M. Lenoir (1989) Linkage analysis of hereditary thyroid carcinoma with and without phenochromocytoma. Hum. Genet. 83, 353–358.
- Norby, S., A. W. S. Sorensen & P. Boesen (1989) Genetic heterogeneity of autosomal dominant polycystic kidney disease. In Genetics of Kidney Disorders, C. Bartsocas (ed.) New York , Alan R. Liss, Inc., pp. 83–88.
- Norum, R. A., R. G. Lafreniere, L. W. O'Neal, T. F. Nikolai, J. P. Delaney, J. C. Sisson, H. Sobol, G. M. Lenoir, B. A. J. Ponder, H. F. Willard & C. E. Jackson (1990) Linkage of the multiple endocrine neoplasia type 2b gene to chromosome 10 markers linked to MEN2A. Genomics (in press).
-
Northrup, H.,
A. L. Beaudet,
W. E. O'Brien,
G. E. Herman,
R. A. Lewis &
M. S. Pollack (1987) Linkage of tuberous sclerosis to ABO blood group.
Lancet
ii, 804.
10.1016/S0140-6736(87)92543-8 Google Scholar
- Ott, J. (1985) Analysis of Human Genetic Linkage Baltimore , Johns Hopkins University Press.
- Piecke, S. A., W. J. Kimberling, J. B. Kenyon & P. Gabow (1989) Genetic heterogeneity of polycystic kindey disease: an estimate of the proportion of families unlinked to chromosome 16. Am. J. Hum. Genet. 45, A58.
- Raeymaekers, P., V. Timmerman, P. De Jonghe, L. Swerts, J. Gheuns, J.-J. Martin, L. Muylle, G. De Winter, A. Vandenberghe & C. Van Broeckhoven (1990) Localization of the mutation in an extended family with Charcot-Marie-Tooth neuropathy. Am. J. Hum. Genet. 45, 953–958.
- Reeders, S. T., M. H. Breuning, K. E. Davies, R. D. Nicholls, A. P. Jarman, D. R. Higgs, P. R. Pearson & D. J. Weatherall (1985) A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317, 542–547.
- Reeders, S. T., M. H. Breuning, M. A. Ryynanen, A. F. Wright, K. E. Davies, A. W. King, M. L. Watson & D. J. Weatherall (1987) A study of genetic linkage heterogeneity in adult polycystic kidney disease. Hum Genet. 76, 348–351.
-
Renwick, J. H. (1987) Tuberous sclerosis and ABO.
Lancet
ii, 1096–1097.
10.1016/S0140-6736(87)91532-7 Google Scholar
- Romeo, G., M. Devoto, G. Costa, L. Roncuzzi, L. Catizione, P. Zuchelli, G. G. Germino, T. Keith, D. J. Weatherall & S. T. Reeders (1988) A second genetic locus for autosomal dominant polycystic kidney disease. Lancet ii, 8–11.
- Rouleau, G. A., W. Wertelecki, J. L. Haines, W. J. Hobbs, J. A. Trofatter, B. R. Seizinger, R. L. Martuza, D. W. Superneau, P. M. Connealy & J. F. Gusella (1987) Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature 329, 246–248.
- Sampson, J. R., J. R. W. Yates, L. A. Pirrit, P. Fleury, I. Winship, P. Beighton & J. M. Connor (1989) Evidence for genetic heterogeneity in tuberous sclerosis. J. Med. Genet. 26, 511–516.
- Smith, M., S. Smalley, R. Cantor, M. Pandolfo, M. I. Gomez, R. Baumann, P. Flodman, K. Yoshiyama, C. Julier, K. Dumars, J. Haines, J. Trofatter, M. A. Spence, D. Weeks & M. Conneally (1990) Mapping of a gene determining tuberous sclerosis to human chromosome 11q14–11q23. Genomics 6, 105–114.
-
Sykes, B.,
D. Ogilvie,
P. Wordsworth &
J. Anderson (1986) Osteogenesis imperfecta is linked to both type I collagen structural genes.
Lancet
ii, 69–72.
10.1016/S0140-6736(86)91609-0 Google Scholar
- Sykes, B., D. Ogilvie, P. Wordsworth, G. Wallis, C. Mathew, P. Beighton, A. Nicholls, F. M. Pope, E. Thompson, P. Tsipouras, R. Schwartz, O. Jensson, A. Arnason, A.-L. Borreson, A. Heiberg, D. Frey & B. Steinmann (1990) Consistent linkage of dominantly inherited osteogenesis imperfecta to the Type 1 collagen loci: COL1A1 and COL1A2. Am. J. Hum. Genet. 46, 293–307.
- Vance, J. M., G. A. Nicholson, L. Yamaoka, J. Stajich, C. S. Stewart, M. C. Speer, W. Y. Hung, A. D. Roses, D. Barker & M. A. Pericak-Vance (1989) Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp. Neurol. 104, 186–189.
- Weeks, D. E. & J. Ott (1990) Risk calculations under heterogeneity. Am. J. Hum. Genet. 45, 819–821.
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