Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.

Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.Coronary artery disease (CAD) due to atherosclerosis results in myocardial infarction (MI) and is the leading cause of death worldwide (1). Epidemiologic studies and clinical intervention trials have established the key roles of specific risk factors for CAD, including smoking, hypertension, high low-density lipoprotein (LDL) cholesterol, high triglycerides, low highdensity lipoprotein (HDL) cholesterol, and diabetes mellitus (2-4). Surprisingly, many of these risk factors cluster with one another more often than expected by chance (5,6). This metabolic syndrome is recognized to be a common cause of CAD; however, the molecular mechanisms that unify their association have been obscure.The marked increase in risk of early cardiovascular mortality to a second monozygotic twin when the first has died from early CAD provides evidence for a strong genetic effect and supports investigation of families with early disease (7). Such studies have the capacity to