Genomic contributions to Mendelian disease
- Johns Hopkins University School of Medicine, McKusick–Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA
This extract was created in the absence of an abstract.
Genomic research has two quite distinct faces. On the one hand, it produces large, curated, reference data sets through numerous networks of investigators for community use—although this aspect has great and widespread utility, it does not inspire per se. On the other hand, it allows an unbiased genome-wide view that is exciting precisely because it habitually uncovers biology that we were hopelessly ignorant about. Consequently, I am sanguine that the search for Mendelian disease genes by exomic and genomic sequencing will produce more than a long and comprehensive list of genes and associated disease mutations. Importantly, we are likely to hear new and surprising biological stories.
Human geneticists have long devoted their energies to understanding, diagnosing, and treating disorders that display a clear and Mendelian (i.e., single-gene) pattern of inheritance. Nevertheless, as Victor McKusick showed through painstaking cataloging, this list of genetic disorders is neither small nor based on extensive genetic evidence (McKusick 1998). Mendelian inheritance of rare traits and diseases has defined patterns of segregation with well-defined quantitative risks of recurrence; but the vast majority of McKusick's entries are based on astute clinical observations of a handful of patients, not extensive quantitative analysis. In other words, in McKusick's catalog, the many rare disorders and syndromes are good hypotheses, not proven examples, of “Mendelian Inheritance in Man.”
This is precisely the situation where a genomic approach is desirable.
Since 2009, technological advancements in sequencing and the ability to select desired segments of the genome have made rapid sequencing of the entire human exome feasible for individual laboratories (Ng et al. 2009). These advances have spurred the discovery of mutations and genes in more than 40 Mendelian disorders using exome and genome sequencing of a small number of cases. Today, any investigator or clinician who has a few well-characterized patients …
