title: The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions.
abstract: OBJECTIVE
  Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.
  
  
  OBJECTIVE
  To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.
  
  
  METHODS
  Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project.
  
  
  METHODS
  We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison.
  
  
  RESULTS
  A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07).
  
  
  CONCLUSIONS
  Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania3Department of Radiology, Geisinger Health System, Danville, Pennsylvania4Program in N.
authors.forename: Andres
authors.initials: A
authors.lastname: Moreno-De-Luca
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg, Pennsylvania5Department of Psychology, Bucknell University, Lewisburg, Pennsylvania.
authors.forename: David W
authors.initials: DW
authors.lastname: Evans
authors.affiliation: Department of Mathematics, Bucknell University, Lewisburg, Pennsylvania.
authors.forename: K B
authors.initials: KB
authors.lastname: Boomer
authors.affiliation: Division of Developmental Medicine, Children's Hospital Boston, Boston, Massachusetts8Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hanson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Goin-Kochel
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg, Pennsylvania11Department of Pediatrics, Geisinger Health System, Danville, Pennsylvania.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Myers
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg, Pennsylvania11Department of Pediatrics, Geisinger Health System, Danville, Pennsylvania.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Challman
authors.affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno-De-Luca
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania.
authors.forename: Mylissa M
authors.initials: MM
authors.lastname: Slane
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania.
authors.forename: Abby E
authors.initials: AE
authors.lastname: Hare
authors.affiliation: Simons Foundation, New York, New York14Department of Pediatrics, Columbia University, New York, New York15Department of Medicine, Columbia University, New York, New York.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Simons Foundation, New York, New York.
authors.forename: John E
authors.initials: JE
authors.lastname: Spiro
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Faucett
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
authors.forename: Christa L
authors.initials: CL
authors.lastname: Martin
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg, Pennsylvania.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000503:physiopathology*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology*; D007360:Intelligence / Q000235:genetics*; D008297:Male; D010290:Parents; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology*; D035781:Siblings; D012919:Social Behavior