Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease.

David N Cooper,Chris Tyler-Smith,Michael Krawczak,Constantin Polychronakos,Hildegard Kehrer-Sawatzki

doi:10.1007/s00439-013-1331-2

Abstract

Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

Highlights

One old conundrum in human genetics is that not everyone with a given pathological mutation will eventually develop the disease in question
We summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease
We present the evidence for reduced penetrance being a widespread phenomenon in human genetics, evidence that comes from a plethora of case studies of monogenic disorders and more recently from the generation sequencing of entire exomes or genomes of apparently normal healthy individuals from the general population

Summary

Introduction

One old conundrum in human genetics is that not everyone with a given pathological mutation (or mutations) will eventually develop the disease in question. The underlying reasons are likely to be many and varied: the variants may damage the protein in question but the intact protein may not be necessary for the health of the carrier; individuals may be asymptomatic carriers of single-mutant alleles that could, in homozygosity or compound heterozygosity, cause recessive disease; the mutation may be dominant but the clinical phenotype might only be mild and classed as lying within the range of normal healthy variation; the disorder might be late in onset with expression being age- or sexdependent; or the disorder may require additional genetic and/or environmental factors for it to manifest clinically. In long QT syndrome, the genotype of a missense polymorphism (Lys897Thr; rs1805123) in the KCNH2 gene appears to distinguish symptomatic from asymptomatic individuals carrying a low-penetrance Ala1116Val pathogenic mutation (Crotti et al 2005) Another example of the modulatory effect of a missense polymorphism on disease allele penetrance is provided by

SCN5A SCN5A TOR1A MEFV MLH1

Findings

Conclusions