Genetic mapping and exome sequencing identify variants associated with five novel diseases

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...

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Published in:	PloS one Vol. 7; no. 1; p. e28936
Main Authors:	Puffenberger, Erik G, Jinks, Robert N, Sougnez, Carrie, Cibulskis, Kristian, Willert, Rebecca A, Achilly, Nathan P, Cassidy, Ryan P, Fiorentini, Christopher J, Heiken, Kory F, Lawrence, Johnny J, Mahoney, Molly H, Miller, Christopher J, Nair, Devika T, Politi, Kristin A, Worcester, Kimberly N, Setton, Roni A, Dipiazza, Rosa, Sherman, Eric A, Eastman, James T, Francklyn, Christopher, Robey-Bond, Susan, Rider, Nicholas L, Gabriel, Stacey, Morton, D Holmes, Strauss, Kevin A
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 17-01-2012 Public Library of Science (PLoS)
Subjects:	Amino Acyl-tRNA Synthetases Amish - genetics Biology Business improvement districts Child Child, Preschool Children Chromosome Mapping - methods Coupling (molecular) CRADD Signaling Adaptor Protein Disease DNA microarrays DNA sequencing Dopamine Plasma Membrane Transport Proteins - genetics Enterprise zones Epilepsy - genetics Ethnic Groups - genetics Exome - genetics Gene mapping Gene polymorphism Gene sequencing Genes Genetic aspects Genetic Association Studies - methods Genetic Predisposition to Disease - genetics Genotyping Haplotypes Hospitals Humans Infant Infant, Newborn Intellectual Disability - genetics Intracellular Signaling Peptides and Proteins - genetics Lists Mapping Medicine Membrane Transport Proteins - genetics Microtubule-Associated Proteins - genetics Mutation Neurosciences Nuclear electric power generation Nuclear Proteins - genetics Parkinsonian Disorders - genetics Pathogenicity Pathogens Polymorphism Polymorphism, Single Nucleotide Population genetics Receptors, Virus - genetics Seizures - genetics Sequence Analysis, DNA - methods Single nucleotide polymorphisms Single-nucleotide polymorphism Usher Syndromes - genetics United States > US Massachusetts Pennsylvania
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: EGP RNJ JTE CF SG DHM KAS. Performed the experiments: EGP RNJ RAW NPA RPC CJF KFH JJL MHM CJM DTN KAP KNW RAS RD EAS JTE CF SR-B. Analyzed the data: EGP RNJ CS KC RAW NPA RPC CJF KFH JJL MHM CJM DTN KAP KNW RAS RD EAS JTE CF SR-B. Contributed reagents/materials/analysis tools: CS KC JTE CF NLR SG DHM KAS. Wrote the paper: EGP RNJ KAS. Delineation of phenotype: NLR DHM KAS. Patient management, collection of samples, and summarization of clinical data: NLR DHM KAS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0028936