Abstract
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.
Highlights
The practice serving Old Order Amish and Mennonite (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 12–14 generations [1,2]
Certain recessive disorders are highly concentrated in Plain sects [3,4]
To assess the utility of exome sequencing in an active clinical setting, we selected 15 patient samples representing 7 different genetic conditions
Summary
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 12–14 generations [1,2]. The overwhelming majority (.99%) 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 (i.e. 10,000 and 50,000 marker) single nucleotide polymorphism (SNP) microarrays with as few as two patients [5]. This is an efficient, low-cost strategy [2]. For 11 (40%) 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
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