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The Clinic for Special Children is a small non-profit pediatric medical facility that specializes in the diagnosis and treatment of genetic disorders among the Amish and Mennonite people of Pennsylvania. Our research leads to the discovery of pathogenic sequence variants and permits the rapid and cost-effective use of molecular genetic testing in our patient population. A current focus of our work is identification of all mutations segregating in the Plain populations of southeastern Pennsylvania for use in diagnostic testing. Presently, over 75 different mutations have been characterized in our patients.
The unique properties of young isolated populations such as the Amish and Mennonites facilitate rapid gene-mapping studies. Disease gene identification strategies, namely candidate gene localization and genome-wide mapping, have been employed with much success using Affymetrix GeneChip microarrays. Over the past 2 years, we have mapped four novel phenotypes and identified the causative gene: (1) sudden infant death with dysgenesis of the testes (SIDDT), (2) cortical dysplasia and focal epilepsy (CDFE), (3) a recessive cardiomyopathy, and (4) LYK5 deficiency. Eight other novel phenotypes have been mapped as well, but the gene has yet to be identified.
In addition to standard genotyping applications, DNA copy number changes are also detectable using SNP microarrays. The clinic laboratory has been exploring the utility of microarray copy number detection for performing “molecular karyotypes.” In our patients, we have detected several chromosomal abnormalities, some of which are below the resolution of standard karyotype analysis.
SNP microarray technology holds great promise as a useful diagnostic tool. The clinic laboratory is currently developing a custom diagnostic microarray that will accommodate several clinical applications on one platform. In addition to genome-wide SNP coverage for disease gene mapping and copy number analyses, this custom microarray will contain all known mutations from the Plain communities, permitting comprehensive molecular genetic testing.