The Plain populations of Pennsylvania are descended from small groups of Swiss immigrants who organized into multiple endogamous demes that have remained genetically isolated over the last 12�C14 generations. Certain ALK5 Inhibitor II recessive disorders are highly concentrated in Plain sects. The overwhelming majority of affected individuals are homozygous for their respective pathogenic variant, which resides within a relatively large, homozygous haplotype block. We have exploited this knowledge to map dozens of recessive conditions using lowdensity single nucleotide polymorphism microarrays with as few as two patients. This is an efficient, low-cost strategy. The ease of genetic mapping is counterbalanced by the difficulty of disease gene identification. Shared homozygous blocks among affected individuals tend to be large and contain dozens or hundreds of genes. Large gene lists are significant obstacles, particularly if XAV939 Wnt/beta-catenin inhibitor expression and functional data provide few clues to prioritize the list. Since 2004, we have mapped loci for 28 genetic disorders within Amish and Mennonite demes. For 11 of these, we could not identify the causative gene as no pathogenic variants were found after sequencing all high-priority candidate genes within the mapped interval. Exome sequencing has recently been shown to expedite disease gene discovery. In a pilot study to investigate the utility of exome sequencing, the Clinic for Special Children and the Broad Institute initiated a collaboration to combine thorough phenotyping, autozygosity mapping, and exome sequencing. Within 12 months, we identified pathogenic variants for seven disorders, six of them novel. To delineate the functional consequences of these variants, we designed and executed studies of mutant protein expression and function. This work highlights the extraordinary potential of next generation technologies for the investigation of monogenic disease among appropriately selected individuals, families, and communities. It provides a realistic model for using next generation sequencing strategies in everyday clinical practice. The phenotype and gene defect for infantile parkinsonism-dystonia have been described elsewhere. Briefly, our patient developed irritability and feeding difficulties soon after birth. Generalized rigidity and dystonia developed during early infancy, impeding motor development, and evolving into severe rigid Parkinsonism by late childhood. The proband cannot speak or use her hands to communicate, and it has thus been difficult to assess cognitive function or thought content. The phenotype and gene defect for infantile parkinsonism-dystonia have been described elsewhere. Briefly, our patient developed irritability and feeding difficulties soon after birth. Generalized rigidity and dystonia developed during early infancy, impeding motor development, and evolving into severe rigid Parkinsonism by late childhood.