Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1991 Apr;48(4):654–661.

Recurrence risk of a new dominant mutation in children of unaffected parents.

E M Wijsman 1
PMCID: PMC1682956  PMID: 2014793

Abstract

Extensions to models originally described by Hartl for predicting the recurrence risk of new dominant mutations are developed in this paper. Additions to the models are (1) possible somatic mosaicism in a parent in some families, (2) the possibility that the parental origin of the mutation may or may not be known, and (3) mutation rates which change as a function of sex and/or time. The models indicate that recurrence risks are most critically affected by (a) the amount of somatic mosaicism which can be tolerated in the parent without manifesting disease and (b) knowledge of the parental origin of the mutation. In addition, there is a moderate effect on recurrence risks if mutation rates increase in the father as a function of time. Recurrence risks are at least as large as the risk of trisomy 21 in a child of a mother of age 35 years or older, probably much higher (5%-10%) when the mutation is known to be of maternal origin or if substantial somatic mosaicism in the parent is compatible with a normal phenotype. The recurrence risk of a new mutation is high because of a very high ascertainment bias of families with substantial germ-line mosaicism.

Full text

PDF
654

Selected References

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

  1. 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]
  2. Byers P. H., Tsipouras P., Bonadio J. F., Starman B. J., Schwartz R. C. Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet. 1988 Feb;42(2):237–248. [PMC free article] [PubMed] [Google Scholar]
  3. Cohn D. H., Starman B. J., Blumberg B., Byers P. H. Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene (COL1A1). Am J Hum Genet. 1990 Mar;46(3):591–601. [PMC free article] [PubMed] [Google Scholar]
  4. Edwards J. H. Familiarity, recessivity and germline mosaicism. Ann Hum Genet. 1989 Jan;53(Pt 1):33–47. doi: 10.1111/j.1469-1809.1989.tb01120.x. [DOI] [PubMed] [Google Scholar]
  5. Emery A. E. Risk estimation in autosomal dominant disorders with reduced penetrance. J Med Genet. 1986 Aug;23(4):316–318. doi: 10.1136/jmg.23.4.316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Friedman J. M. Genetic counseling for autosomal dominant diseases with a negative family history. Clin Genet. 1985 Jan;27(1):68–71. doi: 10.1111/j.1399-0004.1985.tb00186.x. [DOI] [PubMed] [Google Scholar]
  7. Hall J. G., Byers P. H. Genetics of tuberous sclerosis. Lancet. 1987 Mar 28;1(8535):751–751. doi: 10.1016/s0140-6736(87)90396-5. [DOI] [PubMed] [Google Scholar]
  8. Hall J. G., Dorst J. P., Rotta J., McKusick V. A. Gonadal mosaicism in pseudoachondroplasia. Am J Med Genet. 1987 Sep;28(1):143–151. doi: 10.1002/ajmg.1320280121. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Hartl D. L. Recurrence risks for germinal mosaics. Am J Hum Genet. 1971 Mar;23(2):124–134. [PMC free article] [PubMed] [Google Scholar]
  11. Levinson B., Lehesjoki A. E., de la Chapelle A., Gitschier J. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990 Jan;46(1):53–62. [PMC free article] [PubMed] [Google Scholar]
  12. Pauli R. M., Motulsky A. G. Risk counselling in autosomal dominant disorders with undetermined penetrance. J Med Genet. 1981 Oct;18(5):340–343. doi: 10.1136/jmg.18.5.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Reiser C. A., Pauli R. M., Hall J. G. Achondroplasia: unexpected familial recurrence. Am J Med Genet. 1984 Oct;19(2):245–250. doi: 10.1002/ajmg.1320190206. [DOI] [PubMed] [Google Scholar]
  14. Risch N., Reich E. W., Wishnick M. M., McCarthy J. G. Spontaneous mutation and parental age in humans. Am J Hum Genet. 1987 Aug;41(2):218–248. [PMC free article] [PubMed] [Google Scholar]
  15. Thompson E. M., Young I. D., Hall C. M., Pembrey M. E. Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta. J Med Genet. 1987 Jul;24(7):390–405. doi: 10.1136/jmg.24.7.390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES