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

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.

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

“…Sanger sequencing revealed these likely damaging RVs in a number of unaffected relatives (as well as confirming the results of WES), which suggests considerable incomplete penetrance. Cooper et al (2013) recently reviewed incomplete penetrance for many recognized Mendelian disorders and pointed out multiple biological mechanisms may be responsible. For disorders (such as oral clefts) that have a complex and heterogeneous etiology, incomplete penetrance should be expected.…”

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

“…A recent report by Musumeci and coworkers concluded that the most possible explanation for a low frequency of a homozygous c.32-13T>G genotype in Caucasian Pompe patients was reduced or incomplete penetrance, based on the fact that these patients were phenotypically similar to those reported for patients who were compound heterozygous for their c.32-13T>G mutation and another mutation [39]. There are multiple hypotheses for reduced penetrance and efforts are underway to better understand these observations [40]. It seems highly likely that there are many more variables contributing to late-onset disease prediction and manifestation, whereas with severe disease, the presence of two severe mutations in a single gene are most likely to be the sole driving force.…”

A Survey of Methods for Genome Functional Analysis in Comparative Genomics

“…As per another, the 1000 Genomes Project, there are around 20,000-23,000 different ions in synonymous and no synonymous locales of the human genome. Despite the fact that not every one of them are practically important, 530-610 of the variations have useful effect by causing in-frame cancellations and inclusions, untimely stop codons, frame shifts, or by disturbing join locales (4). In spite of various examinations, researchers are as yet confronting a colossal test in unwinding what the succession implies and in choosing whether or not a discovered variation is pathogenic.…”