Copy number variants (CNV) are either hemizygous deletions or local duplications that result in 3 or even 4 copies of a locus45. Five percent of cases of schizophrenia and of autism have each been attributed to CNVs at fewer than a half dozen genomic locations46–48. These effects are less highly penetrant than Mendelian mutations, implying modification by the genetic background. There is no evidence to support the hypothesis that rare single nucleotide variants at the same loci are the major source of genetic variance9, but ongoing deep sequencing studies will quantify such effects. In the case of the ciliopathies, there is evidence from functional assays that rare variants can both promote and modify the severity of disease49. It is thus incontrovertible that rare variants contribute to disease risk, and that identification of such alleles is a powerful mode of genetic analysis. The question is whether they can account for more than a minor fraction of complex disease risk.
