DENVER – Kicking off the annual meeting of the American Society of Human Genetics here on Tuesday, ASHG President Bruce Gelb urged researchers to pay more attention to incomplete penetrance and variable expressivity when applying the results of genetics and genomics to precision medicine.
In his presidential address, delivered to a packed auditorium, Gelb, a professor of pediatrics and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, first acknowledged that this year's event is being somewhat overshadowed by the US presidential election, which "will be a distraction for many of us, possibly for the entirety of our meeting." Nevertheless, he said, "I hope you will join me in trying our best to not let that diminish our engagement with the many scientific opportunities here for us this week."
Drawing participants' attention to penetrance — the probability that an individual with a pathogenic variant for a Mendelian, or single-gene, disorder actually develops that disease — and expressivity — the degree to which a trait is expressed differently between affected individuals — he suggested that the two concepts are sometimes misapplied in population genomic screening, which has been enabled by the ever-decreasing price of genomic sequencing.
To explain this, he contrasted penetrance of a gene-trait pair as defined by studies of families affected by a Mendelian disorder, or "penetrance familial," with penetrance defined through genotype-first population studies, or "penetrance population." For most traits studied to date, he said, the two are not the same, and "penetrance population" is usually lower than "penetrance familial," with rare exceptions. The same is true for expressivity, he added, which also often shows greater variability in studies of affected families than in population-based ones.
Historically, he said, "penetrance" and "expressivity" can be traced back to a German researcher who coined the terms in a paper published in the 1920s, applying them to a fruit fly trait. However, that researcher did not distinguish between genes and alleles — suggesting that penetrance is equal for all alleles of a gene, which Gelb said is not true — and did not pay attention to the fact that penetrance for the trait in question depended on the genetic background of the flies. These misconceptions have survived to this day.
"The promise of precision medicine requires that we correct errors in our understanding of penetrance and expressivity made nearly 100 years ago that continue to reverberate among us today," Gelb said.
What contributes to the variability in penetrance and expressivity, he said, are genetic factors, environmental contributors, including epigenetic marks, and randomness or stochasticity, each of which other talks during the conference will further discuss.
With regard to environmental factors at play, he pointed to so-called "norms of reaction," a term used both in ecology and genetics that describe the expression of a genotype in different environments. Individuals with cystic fibrosis, for example, show differences in lung function depending on the climate temperature where they live. "We need to bring back the concept of norms of reaction to our field and grapple with their importance for understanding Mendelian traits," Gelb said.
"As scientists in the field of human genetics and genomics, we have both challenges and opportunities to enable the full potential of precision medicine," he said. "We need to elaborate 'penetrance population' for Mendelian traits for which we feel population screening or return of results are worthwhile."