Genotype–Phenotype Relationships


Many diseases due to a single defective gene show wide clinical variability. This results from the interaction of a number of other modifying genes, variability in adaptive mechanisms and the effects of the environment. Less commonly, phenotypic diversity reflects peculiarities in the distribution of mutations in mitochondrial deoxyribonucleic acid (DNA) or from mutations at different genes that result in a similar but highly variable clinical disorder. The multilayer complexity of this type of genetic system is only just starting to be appreciated, but provides some indication of the problems that will be encountered in analysing common multigenic disease. Their solution has important implications for the future practice of clinical genetics. Accurate phenotype prediction is essential for all aspects of genetic counselling, particularly in cases where couples are being advised about the likely outcome of a serious genetic disease if they are being offered the possibility of prenatal diagnosis and potential termination of affected pregnancies.

Key concepts

  • Most genetic diseases that follow a Mendelian pattern of inheritance show considerable clinical (phenotypic) diversity.

  • In many cases phenotypic diversity of Mendelian disease can be explained by the heterogeneity of mutations at a particular locus.

  • Phenotypic diversity of Mendelian disease may also result from the action of modifier genes that increase or decrease the severity of the effect of the primary mutation or which act at a distance from the mutation in further modifying the complications of the disease.

  • The clinical features of a single‐gene disorder may also be modified by variation in X‐chromosome inactivation, genomic imprinting and other epigenetic factors.

  • An increasing number of monogenic neurological diseases are being identified which result from variable degrees of expansion of repeat elements within or close to particular genes.

  • Many common diseases such as heart disease, stroke and diabetes result from the interaction of environmental factors with genetic susceptibility which is mediated through polymorphisms of a variable number of different genes.

  • The phenotypic effects of drug administration, both efficacy and complications, are modified by genes involving a wide range of physiological functions.

  • The vast majority of common forms of cancer are caused by mutations of cellular oncogenes which occur during an individuals lifetime.

  • Individual variability and the likelihood of contracting communicable disease, and its clinical course, also reflects the action of a wide variety of genes.

  • Future dissection of the complex interactions between the genome and the environment in the case of both monogenic and multigenic disease has the potential for improving the public health control of these diseases and for developing new therapeutic agents.

Keywords: genotype; phenotype; genetic disease


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How to Cite close
Weatherall, David J(Mar 2009) Genotype–Phenotype Relationships. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003403.pub2]