title: Genetic mapping and exome sequencing identify variants associated with five novel diseases.
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.
authors.affiliation: Clinic for Special Children, Strasburg, Pennsylvania, United States of America. epuffenberger@clinicforspecialchildren.org
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jinks
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Willert
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Achilly
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Cassidy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fiorentini
authors.forename: Kory F
authors.initials: KF
authors.lastname: Heiken
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: Lawrence
authors.forename: Molly H
authors.initials: MH
authors.lastname: Mahoney
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Devika T
authors.initials: DT
authors.lastname: Nair
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Politi
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Worcester
authors.forename: Roni A
authors.initials: RA
authors.lastname: Setton
authors.forename: Rosa
authors.initials: R
authors.lastname: Dipiazza
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sherman
authors.forename: James T
authors.initials: JT
authors.lastname: Eastman
authors.forename: Christopher
authors.initials: C
authors.lastname: Francklyn
authors.forename: Susan
authors.initials: S
authors.lastname: Robey-Bond
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Rider
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
mesh_terms: D000604:Amino Acyl-tRNA Synthetases; D061365:Amish / Q000235:genetics; D053420:CRADD Signaling Adaptor Protein; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D059472:Exome / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D011991:Receptors, Virus / Q000235:genetics; D012640:Seizures / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D052245:Usher Syndromes / Q000235:genetics
chemical_list: C573230:BRAT1 protein, human; D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; C492690:FLVCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011991:Receptors, Virus; C493214:SLC6A3 protein, human; C411545:SNIP1 protein, human; C444456:TUBGCP6 protein, human; D000604:Amino Acyl-tRNA Synthetases; C093612:HARS2 protein, human