title: Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment.
abstract: Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1."
authors.affiliation: Department of Genetics, Yale University, 464 Congress Avenue, Suite 243, New Haven, CT 06520, USA.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Powers
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.forename: Falk
authors.initials: F
authors.lastname: Butter
authors.forename: Yong
authors.initials: Y
authors.lastname: Kong
authors.forename: Laura L
authors.initials: LL
authors.lastname: Miller
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gruen
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D004410:Dyslexia / Q000235:genetics*; D056726:Genetic Association Studies; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics*; D007807:Language Tests; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D008869:Microtubule-Associated Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C510451:DCDC2 protein, human