1. Academic Validation
  2. Genetic mapping and exome sequencing identify variants associated with five novel diseases

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

  • PLoS One. 2012;7(1):e28936. doi: 10.1371/journal.pone.0028936.
Erik G Puffenberger 1 Robert N Jinks Carrie Sougnez Kristian Cibulskis Rebecca A Willert Nathan P Achilly Ryan P Cassidy Christopher J Fiorentini Kory F Heiken Johnny J Lawrence Molly H Mahoney Christopher J Miller Devika T Nair Kristin A Politi Kimberly N Worcester Roni A Setton Rosa Dipiazza Eric A Sherman James T Eastman Christopher Francklyn Susan Robey-Bond Nicholas L Rider Stacey Gabriel D Holmes Morton Kevin A Strauss
Affiliations

Affiliation

  • 1 Clinic for Special Children, Strasburg, Pennsylvania, United States of America. epuffenberger@clinicforspecialchildren.org
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.

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