title: DUF1220 dosage is linearly associated with increasing severity of the three primary symptoms of autism.
abstract: One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD.
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America; Medical Scientist Training Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Veronica B
authors.initials: VB
authors.lastname: Searles
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Keeney
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Dumas
authors.affiliation: Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Sikela
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D017434:Protein Structure, Tertiary