Assessment of heritable genetic effects using new genetic tools and sentinels in an era of personalized medicine

Abstract

The challenge of estimating human health effects from damage to the germ line may be met in the genomic era. Understanding the genetic, as opposed to postconception developmental basis of birth defects is critical to their use in monitoring heritable genetic damage. The causes of common birth defects are analyzed here: mendelian genetic, multigenic, developmental, inherited, or combinational. Only a small fraction of these (noninherited, mendelian genetic) are likely to be informative relative to germ cell mutagenesis, and these won't be discernible against the general background of birth defects. Targeted genetic testing as part of personalized medicine could be integrated into a strategy for assessing germ cell alterations in populations. Thus, "sentinel mutations," as originally proposed by Mulvihill and Ceizel, need not be restricted to X-linked or dominant mutations or conditions visible at birth. Several new sentinels related to personalized medicine are proposed, based on health impact (likelihood of monitoring), frequency, and genetic target suitability (responsiveness to diverse mutational mechanisms). Candidates could include CYP genes (related to metabolism of xenobiotics) important in optimizing drug doses and avoiding adverse reactions. High frequency LDLR mutations (related to familial high cholesterol) predict myocardial infarction in approximately50% of individuals. The more common recessive genetic diseases (cystic fibrosis, phenylketonuria, and others) monitored in newborn screening programs could be informative given parental analysis. New opportunities for genetic analyses need to be coupled with epidemiological studies on environmental exposures. These could focus on adverse outcomes related to tobacco, the mostubiquitous and potent environmental mutagen.

Descriptive epidemiology of birth defects thought to arise by new mutation

“…Olshan () stated that “despite the fact that radiation and chemically induced germ cell damage has been repeatedly demonstrated in mammals and other experimental organisms, the detection of these induced mutations and disease in offspring in humans has been limited. A single, convincing case of an environmentally related exposure causing birth defects, cancer, or other diseases in offspring by means of germ cell mutations has not been recognized.” This was echoed by Elespuru () and potential reasons have been suggested by Elespuru and Sankaranarayanan () and Wyrobek et al (). For example, Sankaranarayanan () proposed that most radiation‐induced mutations (predominantly multigene deletions) are different from spontaneous mutations (among which are point mutations and DNA deletions within a gene) and are not compatible with embryonic viability sufficiently to be recognized in humans.…”

“…However, alternative approaches that have been suggested for estimating the human mutation rate such as understanding DNA biochemistry or interspecies variation are not useful for public health purposes, and genomic sequence analysis is not yet feasible for large populations. The latter may become more practical with increasing use of personalized medicine (related to individual genetic differences and targeted therapies) or screening of newborns for increasing numbers of genetic tests (Elespuru, ).…”

Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations

“…A critical question relates to whether adverse reproductive endpoints in humans, which are found in ∼4% of live births, are related to genetic (germ cell) damage, epigenetic effects, or non‐genetic developmental outcomes. The vast majority of adverse human birth outcomes are inherited or caused by non‐disjunction events in aging ova, but most of these can be quite readily removed from consideration when evidence for genomic (and now more recently epigenetic) damage is sought [Elespuru, ].…”