Genetic Risk: Computation


Despite the progress of molecular genetics and the resulting improved possibilities for precise risk classification in affected families, the principles of formal risk assessment continue to be of great importance as a decision‐making aid for a targeted molecular genetic analysis and an adequate interpretation of molecular findings. Assuming a genetic model, which is both the basis for risk assessment and the interpretation of molecular findings is of great importance. Even in the molecular era Bayesian theorem has to be applied in monogenetic diseases like Huntington disease, spinal muscular atrophy and Duchenne muscular dystrophy. Precise risk assessment in genetic counseling often deserves Bayesian risk calculation.

Key Concepts

  • Risk assessment in families with genetic diseases is of great importance in spite of improved molecular diagnostics.
  • Risk assessment is important for both the indication of molecular diagnostics and the interpretation of possible molecular findings.
  • The prerequisite for the risk assessment is the assumption of a specific genetic model.
  • Taking a larger number of variables (e.g. incomplete penetrance, spontaneous mutations and late onset) into account, risk calculation can significantly modify a priori risks.

Keywords: risk calculation; Bayes' theorem; Mendelian inheritance; genetic model; linked markers; penetrance; risk function

Figure 1. Autosomal inheritance with incomplete penetrance. Caesar and Doris are asking for an assessment of the risk of having an affected child.
Figure 2. Risk of being affected, for a child of the healthy offspring of an affected person with an autosomal dominant trait with incomplete penetrance.
Figure 3. Autosomal dominant inheritance with late onset. Ernst is asking for an assessment of his risk of being a heterozygote.
Figure 4. Autosomal recessive inheritance. Doris, the sister of an affected brother (Caesar), is asking for an assessment of her risk of having an affected child.
Figure 5. X‐linked recessive inheritance; DMD.


Barbujani G, Russo A, Danieli GA, et al. (1990) Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases. Human Genetics 84: 522–526.

Deburgrave N, Daoud F, Llense S, et al. (2007) Protein‐ and mRNA‐based phenotype‐genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene. Human Mutation 28: 183–195.

Dunnen JT, Grootscholten PM, Bakker E, et al. (1989) Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. American Journal of Human Genetics 45: 835–847.

Emery AE (1991) Population frequencies of inherited neuromuscular diseases – a world survey. Neuromuscular Disorders 1: 19–29.

Grimm T (1984) Genetic counseling in Becker type X‐linked muscular dystrophy. I. Theoretical considerations. American Journal of Medical Genetics 18: 713–718.

Grimm T, Müller B, Müller CR and Janka M (1990) Theoretical considerations on germline mosaicism in Duchenne muscular dystrophy. Journal of Medical Genetics 27: 683–687.

Grimm T, Meng G, Liechti‐Gallati S, et al. (1994) On the origin of deletions and point mutations in Duchenne muscular dystrophy (DMD): most deletions arise in oogenesis and most ‘point mutations’ are due to events in spermatogenesis. Journal of Medical Genetics 31: 183–186.

Grimm T, Kress W, Meng G and Müller CR (2012) Risk assessment and genetic counseling in families with Duchenne muscular dystrophy. Acta Myologica 31: 179–183.

Haldane JBS (1935) The rate of spontaneous mutations of a human gene. Journal of Genetics 31: 317–326.

Hardy GH (1908) Mendelian proportions in a mixed population. Science 28: 49–50.

Kawamura J, Kato S, Ishihara T, Hiraishi Y and Kawashiro T (1997) Difference of new mutation rates in dystrophin gene between deletion and duplication mutation in Duchenne and Becker muscular dystrophy. Rinshō Shinkeigaku 37: 212–217.

Keller H, Emery AEH, Spiegler AWJ, et al. (1996) Age effects on serum creatine kinase (SCK) levels in obligate carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) and its implication on genetic counselling. Acta Cardiomyologica 8: 27–34.

Langer S, Rudnik‐Schöneborn S, Zerres K and Grimm T (2013) Genetisches Modell der autosomal‐rezessiv erblichen proximalen spinalen Muskelatrophie. MedGen 25: 337–346.

Newcombe RG (1981) A life table for onset of Huntington's chorea. Annals of Human Genetics 45: 375–385.

Ogino S, Wilson RB and Gold B (2004) New insights on the evolution of the SMN1 and SMN2 region: simulation and meta‐analysis for allele and haplotype frequency calculations. European Journal of Human Genetics 12: 1015–1023.

Pauli RM and Motulsky AG (1981) Risk counselling in autosomal dominant disorders with undetermined penetrance. Journal of Medical Genetics 18: 340–343.

Weinberg W (1908) Über den Nachweis der Vererbung beim Menschen. Jahreshefte des Vereins für vaterländische Naturkunde in Württemberg 64: 368–382.

White SJ, Aartsma‐Rus A, Flanigan KM, et al. (2006) Duplications in the DMD gene. Human Mutation 27: 938–945.

Further Reading

Bickeböller H and Fischer C (2007) Einführung in die Genetische Epidemiologie (Statistik und ihre Anwendungen). Heidelberg, Germany: Verlag: Springer.

Bridge PJ (1994) The Calculation of Genetic Risks. Baltimore, MD: Johns Hopkins University Press.

Lathrop GM and Lalouel JM (1984) Easy calculations of lod scores and genetic risks on small computers. American Journal of Human Genetics 36: 460–465.

Young ID (1991) Introduction to Risk Calculation in Genetic Counselling. Oxford, UK: Oxford University Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Grimm, Tiemo, Müller‐Myhsok, Bertram, and Zerres, Klaus(Oct 2017) Genetic Risk: Computation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005433.pub2]