Mendelian Puzzles

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Science  24 Feb 2012:
Vol. 335, Issue 6071, pp. 930-931
DOI: 10.1126/science.1219301

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Mendelian genetic disorders, rare clinical phenotypes arising from a single-gene mutation, are extremely diverse traits that affect every organ system, age group, and human population (1). Their cumulative incidence is rare (under 5%) because the clinical phenotypes are deleterious and affected individuals rarely reproduce. They persist in the population by de novo mutation in the past few generations, but some recessive mutations are an exception because their effects can be sheltered in carriers for hundreds of generations. Identifying the genes and mutations for over 2500 Mendelian disorders—one of the early fruits of the Human Genome Project (2)—has been recently spectacularly advanced by sequencing entire exomes (the protein-coding content of the genome) (3). Nevertheless, we will need to closely examine gene-regulatory sequences to understand the full spectrum of Mendelian phenotypic variation. Indeed, on page 966 of this issue, Lee et al. (4) demonstrate that a disorder called Joubert syndrome is caused by mutations in either of two different, adjacent genes that share a common regulatory region (constituting a so-called cisregulatory module). This is one example of how human genetics is maturing from a focus on single genes into a more genomic view.