Relation of Animal Studies to the Problem in Man

  • F. Clarke Fraser


By “the problem” in man we refer to the fact that some 3–7% of human babies are born with malformation serious enough to require treatment. Etiologically these can be broken down into five categories: those caused by a mutant gene (roughly 5%), those in which there is evidence for a multifactorial basis (roughly 20%), those associated with a chromosomal aberration, either autosomal (2%) or sex-chromosomal (8%), those caused by an identifiable environmental agent (roughly 5%), and those in which no cause has been identified (roughly 60%).


Club Foot Cleft Palate Cleave Palate Face Shape Hypertrophic Pyloric Stenosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Biddle, F. G., 1975, Teratogenesis of acetazolamide in the CBA/J and SWV strains of mice II. Genetic control of the teratogenic response, Teratology 11: 37.CrossRefGoogle Scholar
  2. Bonaiti-Pellié, C., and Smith, C., 1974, Risk tables for counselling in some common congenital malformations, J. Med. Genet. 11: 374.CrossRefGoogle Scholar
  3. Braithwaite, F., and Watson, J., 1949, A report on three unusual cleft lips, Br. J. Plast. Surg. 2: 38.CrossRefGoogle Scholar
  4. Carter, C. O., 1961, The inheritance of congenital pyloric stenosis, Br. Med. Bull. 17 (3): 251.Google Scholar
  5. Carter, C. O., 1969, Genetics of common disorders, Br. Med. Bull. 25 (1): 52.Google Scholar
  6. Carter, C. O., 1976, Genetics of common single malformations, Br. Med. Bull. 32: 21.Google Scholar
  7. Carter, C. O., and Evans, K., 1973, Spina bifida and anencephalus in Greater London, J. Med. Genet. 10 (3): 209.CrossRefGoogle Scholar
  8. Carter, T. C., 1959, Embryology of the Little and Bagg X-rayed mouse stock, J. Genet. 56 (3): 401.CrossRefGoogle Scholar
  9. Cavalli-Sforza, L. L., and Bodmer, W. F., 1971, The Genetics of Human Populations, W. H. Freeman, San Francisco.Google Scholar
  10. Coccaro, P. J., D’Amico, R., and Chavoor, A., 1972, Craniofacial morphology of parents with and without cleft lip and palate children, Cleft Palate J. 9: 23.Google Scholar
  11. Dagg, C. P., Schlager, G., and Doerr, A., 1965. Polygenic control of the teratogenicity of 5-fluorouracil in mice, Genetics 53 (6): 1101.Google Scholar
  12. Davidson, J. G., Fraser, F. C., and Schlager, G., 1969, A maternal effect on the frequency of spontaneous cleft lip in the A/J mouse, Teratology 2 (4): 371.CrossRefGoogle Scholar
  13. deMyer, W., Zeman, W., and Palmer, C. G., 1964, The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arrhinencephaly), Pediatrics 34 (2): 256Google Scholar
  14. Deol, M. S., 1961, Genetical studies on the skeleton of the mouse XXVIII. Tail-short, Proc. R. Soc. (London), Ser. B 155: 78.CrossRefGoogle Scholar
  15. Deol, M. S., 1973, An experimental approach to the understanding and treatment of hereditary syndromes with congenital deafness and hypothyroidism, J. Med. Genet. 10 (3): 235.CrossRefGoogle Scholar
  16. Ede, D. A., and Agerback, G. S., 1968, Cell adhesion and movement in relation to the developing limb pattern in normal and talpid3 mutant chick embryos, J. Embryol. Exp. Morphal. 20 (1): 81.Google Scholar
  17. Ede, D. A., and Kelley, W. A., 1964a, Developmental abnormalities in the head region of the talpid3 mutant of the fowl, J. Embryol. Exp. Morphol. 12: 161.Google Scholar
  18. Ede, D. A., and Kelley, W. A., 1964b, Developmental abnormalities in the trunk and limbs of the talpid3 mutant of the fowl. J. Embryol. Exp. Morphol. 12: 339.Google Scholar
  19. Edwards, J. H., 1969, Familial predisposition in man, Br. Med. Bull. 25 (1): 58.Google Scholar
  20. Elston, R. C., and Yelverton, K. C., 1975, General models for segregation analysis, Am. J. Hum. Genet. 27: 31.Google Scholar
  21. Erway, L. C., Fraser, A. S., and Hurley, L. C., 1971, Prevention of congenital otolith defect in pallid mutant mice by manganese supplementation, Genetics 67: 97.Google Scholar
  22. Falconer, D. S., 1965, The inheritance of liability to certain diseases estimated from the incidence among relatives, Ann. Hum. Genet. 29: (1): 51.CrossRefGoogle Scholar
  23. Falconer, D. S., 1967, The inheritance of liability to diseases with variable age of onset, with particular reference to diabetes mellitus, Ann. Hum. Genet. Lond. 31 (1): 1.Google Scholar
  24. Fraser, F. C., 1959, Antenatal factors in congenital defects. Problems and pitfalls, N.Y. State of J. Med. 59 (8): 1597.Google Scholar
  25. Fraser, F. C., 1961, The use of teratogens in the analysis of abnormal development mechanisms, in: First International Conference on Congenital Malformation Genetics ( M. Fishbein, ed.), pp. 179–186, J. B. Lippincott, Philadelphia.Google Scholar
  26. Fraser, F. C., 1963, Hereditary disorders of the nose and mouth, in: Proceedings of the Ilnd International Conference on Human Genetics ( L. Gedda, ed.), Vol. 2, pp. 1852–1855, Instituto G. Mendel, Rome.Google Scholar
  27. Fraser, F. C., 1964, Experimental teratogenesis in relation to congenital malformations in man, in: Proceedings of the 2nd International Conference on Congenital Malformations ( M. Fishbein, ed.), pp. 277–287, International Medical Congress Ltd., New York.Google Scholar
  28. Fraser, F. C., 1965, Some genetic aspects of teratology, in: Teratology, Principles and Techniques ( J. G. Wilson and J. Warkany, eds.), pp. 21–38, University of Chicago Press, Chicago.Google Scholar
  29. Fraser, F. C., 1969, Gene—environment interactions in the production of cleft plate, in: Methods for Teratological Studies in Experimental Animals and Man ( H. Nishimura and J. R. Miller, eds.), pp. 34–49, Igaku Shoin Ltd., Tokyo.Google Scholar
  30. Fraser, F. C., 1970, The genetics of cleft lip and cleft palate, Am. J. Hum. Genet. 22 (3): 336.Google Scholar
  31. Fraser, F. C., 1976, Uses and misuses of the multifactorial/threshold concept, Teratology 13 (in press).Google Scholar
  32. Fraser, F. C., and Fainstat, T. D., 1951, The production of congenital defects in the offspring of pregnant mice treated with cortisone. A progress report, Pediatrics 8: 527.Google Scholar
  33. Fraser, F. C., and Nora, J. J., 1975, Genetics of Man, Lea and Febiger, Philadelphia, Chapter 11.Google Scholar
  34. Fraser, F. C., and Pashayan, H., 1970, Relation of face shape to susceptibility to congenital cleft lip. A preliminary report, J. Med. Genet. 7 (2): 112.CrossRefGoogle Scholar
  35. Fraser, F. C., and Rosen, J., 1975, Association of cleft lip and atrial septal defect in the mouse,Teratology 11: 321.CrossRefGoogle Scholar
  36. Gold, R. J. M., and Scriver, C. R., 1972, Properties of hair keratin in an autosomal dominant form of ectodermal dysplasia, Am. J. Hum. Genet. 24: 549.Google Scholar
  37. Goltz, R. W., Henderson, R. R., Hitch, J. M., and Ott, J. E., 1970, Focal dermal hypoplasia syndrome, Arch. Derm. 101 (1): 1.CrossRefGoogle Scholar
  38. Gray, I. M., Lowry, R. B., and Renwick, D. H. G., 1972, Incidence and genetics of Legg—Perthes disease (osteochondritis deformans) in British Columbia: Evidence of polygenic determination, J. Med. Genet. 9: 197.CrossRefGoogle Scholar
  39. Green, M. C., 1968, Mechanism of the pleiotropic effects of the short-ear mutant gene in the mouse, J. Exp. Zool. 167 (2): 129.CrossRefGoogle Scholar
  40. Gruneberg, H., 1952, Genetical studies on the skeleton of the mouse. IV. Quasi-continuous variations, J. Genet. 51: 95.CrossRefGoogle Scholar
  41. Gruneberg, H., 1960, Genetical studies on the skeleton of the mouse. XXV. The development of syndactylism, Genet. Res. 1 (2): 196.CrossRefGoogle Scholar
  42. Gruneberg, H., 1963, The Pathology of Development, Blackwells, Oxford, U.K.Google Scholar
  43. Harris, M. W., and Fraser, F. C., 1968, Lid gap in newborn mice: A study of its cause and prevention, Teratology 1 (4): 417.CrossRefGoogle Scholar
  44. Johnston, M. C., and Listgarten, M. A., 1972, The migration, interaction and early differentiation of oro-facial tissues, in: Development Aspects of Oral Biology ( H. S. Slavkin and L. A. Baretta, eds.) p. 53, Academic Press, New York.Google Scholar
  45. Jones, K. L., Smith, D. W., Hall, B. D., Hall, J. G., Ebbin, A. J., Massoud, H., and Golbus, M.S., 1974, A pattern of cranio-facial and limb defects secondary to aberrant tissue bands, J. Pediatr. 84: 90.CrossRefGoogle Scholar
  46. Juriloff, D. M., and Trasler, D. G., 1976, Test of the hypothesis that embryonic face shape is a factor in genetic predisposition to cleft lip in mice, Teratology 13 (in press).Google Scholar
  47. Kurisu, K., Niswander, J. D., Johnston, M. C., and Mazaheri, M., 1974, Facial morphology as an indicator of genetic predispositions to cleft lip and palate, Am. J. Hum. Genet. 26: 702.Google Scholar
  48. Landauer, W., 1955, Recessive and sporadic rumplessness of fowl: Effects on penetrance and expressivity, Am. Nat. 89: 35.CrossRefGoogle Scholar
  49. Larsson, K. S., 1962, Studies on the closure of the secondary palate. IV. Autoradiographic and histochemical studies of mouse embryos from cortisone-treated mothers, Acta Morphol. Neerl.-Scand. 4: 369.Google Scholar
  50. Mendell, N. R., and Elston, R. C., 1974, Multifactorial qualitative traits: Genetic analysis and prediction of recurrence risks, Biometrics 30: 41.CrossRefGoogle Scholar
  51. Morton, N. E., Yee, S., Elston, R. C., and Lew, R., 1970, Discontinuity and quasi-continuity: Alternative hypotheses of multifactorial inheritance, Clin. Genet. 1: 81.CrossRefGoogle Scholar
  52. Newcombe, H. B., 1963, The phenodeviant theory, in: Congenital malformations ( M. Fishbein, ed.), pp. 345–349, International Medical Congress Ltd., New York.Google Scholar
  53. Nora, J. J., 1971, Etiologic factors in congenital heart disease, Pediatr. Clin. North Am. 18 (4): 1059.Google Scholar
  54. Nora, J. J., Sommerville, R. J., and Fraser, F. C., 1968, Homologies for congenital heart diseases: Murine models, influenced by dextroamphetamine, Teratology 1 (4): 413.CrossRefGoogle Scholar
  55. Passarge, E., 1973, Genetics of Hirschsprung’s disease, Clin. Gastroenterol. 2 (3): 507.Google Scholar
  56. Poswillo, D., 1966, Observations of fetal posture and causal mechanisms of congenital deformity of palate, mandible, and limbs. J. Dent. Res. 45 (Suppl. 3): 584.CrossRefGoogle Scholar
  57. Poswillo, D., 1973. The pathogenesis of the first and second branchial arch syndrome, Oral Surg., Oral Med., Oral Pathol. 35: 302.CrossRefGoogle Scholar
  58. Poswillo, D., 1975, The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis), Br. J. Oral Surg. 13: 1.CrossRefGoogle Scholar
  59. Rice, J. M., 1973, An overview of transplacental chemical carcinogenesis, Teratology 8: 113.CrossRefGoogle Scholar
  60. Sang, J. H., 1963, Penetrance, expressivity and thresholds, J. Hered. 54 (4): 143.CrossRefGoogle Scholar
  61. Shih, L. Y., Trasler, D. G., and Fraser, F. C., 1974, Relation of mandible growth to palate closure, Teratology 9: 191.CrossRefGoogle Scholar
  62. Sisken, B. F., and Gluecksohn-Waelsch, S., 1959, A developmental study of the mutation “Phocomelia” in the mouse, J. Exp. Zool. 142 (1,2,3,): 623.CrossRefGoogle Scholar
  63. Smith, C., 1971, Recurrence risks for multifactorial inheritance, Am. J. Hum. Genet. 23 (6): 578.Google Scholar
  64. Smith, C., 1974, Concordance in twins: Methods and interpretation, Am. J. Hum. Genet. 26 (4): 454.Google Scholar
  65. Tenenhouse, H. S., Gold, R. J. M., Kachra, Z., and Fraser, F. C., 1974, Biochemical marker in dominantly inherited ectodermal malformation, Nature 251: 431.CrossRefGoogle Scholar
  66. Trasler, D. G., 1965, Strain differences in susceptibility to teratogenesis, Survey of spontaneously occurring malformations in mice, in: Teratology ( J. G. Wilson and J. Warkany, eds.), pp. 38–55, Univ. of Chicago Press, Chicago.Google Scholar
  67. Trasler, D. G., 1968, Pathogenesis of cleft lip and its relation to embryonic face shape in A/J and C57BL mice, Teratology 1 (1): 33.CrossRefGoogle Scholar
  68. Trasler, D. G., and Fraser, F. C., 1958, Factors underlying strain, reciprocal cross, and maternal weight differences in embryo susceptibility to cortisone induced cleft palate in mice, Proc. X Int. Cong. Genet. 2: 296.Google Scholar
  69. Trasler, D. G., and Fraser, F. C., 1963, Role of the tongue in producing cleft palate in mice with spontaneous cleft lip, Dey. Biol. 6: 45.CrossRefGoogle Scholar
  70. Trasler, D. G., Walker, B. E., and Fraser, F. C., 1956, Congenital malformations produced by amniotic-sac puncture, Science 124: 439.CrossRefGoogle Scholar
  71. Verrusio, A. C., 1966, Biochemical basis for a genetically determined difference in response to the teratogenic effects of 6-aminonicotinamide, Ph. D. thesis, McGill University, Montreal, Canada.Google Scholar
  72. Walker, B. E., and Fraser, F. C., 1956, Closure of the secondary palate in three strains of mice, J. Embryol. Exp. Morphol. 4: 176.Google Scholar
  73. Walker, B. E., and Fraser, F. C., 1957, The embryology of cortisone-induced cleft palate, J. Embryol. Exp. Morphol. 5 (2): 201.Google Scholar
  74. Watney, M., and Miller, J. R., 1964, Prevention of a genetically determined congenital eye anomaly in the mouse by the administration of cortisone during pregnancy, Nature 202 (4936): 1029.CrossRefGoogle Scholar
  75. Weinstein, E. D., and Cohen, M. M., 1966, Sex-linked cleft palate—report of a family and review of 77 kindreds, J. Med. Genet. 3 (1): 1.CrossRefGoogle Scholar
  76. Williams, M., and Fraser, F. C., 1966, Hydrotic ectodermal dysplasia—Clouston’s family revisited, Can. Med. Assoc. J. 96: 377.Google Scholar
  77. Wright, S., 1934, The results of crosses between inbred strains of guinea pigs, differing in number of digits, Genetics 19: 537.Google Scholar
  78. Wynne-Davies, R., 1965, Family studies and aetiology of club foot, J. Med. Genet. 2 (4): 227.CrossRefGoogle Scholar
  79. Wynne-Davies, R., 1970, A family study of neonatal and late-diagnosis congenital dislocation of the hip, J. Med. Genet. 7 (4): 315.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • F. Clarke Fraser
    • 1
    • 2
  1. 1.Department of BiologyMcGill UniversityMontrealCanada
  2. 2.Department of Medical GeneticsThe Montreal Children’s HospitalMontrealCanada

Personalised recommendations