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Cited by 137Genomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental DisordersWilliams Syndrome Research

The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions

Moreno-De-Luca, Andres, Evans, David W., Boomer, K. B., Hanson, Ellen, Bernier, Raphael, Goin-Kochel, Robin P., Myers, Scott M., Challman, Thomas D. +8 more·2015·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2014.2147
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Abstract

IMPORTANCE: 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. OBJECTIVES: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

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  • Common variant-related polygenic risk and rare inherited variants in the genetic background also impact the phenotypic expression of rare, large-effect pathogenic variants in NDDs.

    “Common variant-related polygenic risk and rare inherited variants in the genetic background also impact the phenotypic expression of rare, large-effect pathogenic variants in NDDs”

    From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [47]

  • 22q11.2 and 16p11.2 deletions are associated with variable severity with various neuropsychiatric disorders, including ASD, intellectual disability, and schizophrenia.

    “Both deletions are in fact associated, with variable severity, with various neuropsychiatric disorders, including ASD, ID and schizophrenia, among others (50,96).”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [50]

  • The same study showed the value of using quantitative rather than dichotomous measures to assess and account for familial influence.

    “and shown the value of using quantitative rather than dichotomous measures to better assess and account for such familial influence (50).”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [50]

  • Common variation may determine which specific traits are expressed when a highly penetrant mutation occurs, and findings in 22q11.2 and 16p11.2 deletion syndromes provide some support for this.

    “One intriguing hypothesis is that common variation may be a factor determining the expression of specific traits when a highly penetrant mutation occurs (Fig. 1), and recent findings in both 22q11.2 and 16p11.2deletion syndromes provide some support of this.”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [50]

  • 22q11.2 and 16p11.2 deletions can also be found in healthy individuals, which is consistent with incomplete penetrance.

    “The deletions can also be detected in healthy individuals, an observation consistent with incomplete penetrance (50,96)”

    From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [50]

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Authors
Moreno-De-Luca, A., Evans, D. W., Boomer, K. B., Hanson, E., Bernier, R., Goin-Kochel, R. P., Myers, S. M., Challman, T. D., Moreno-De-Luca, D., Slane, M. M., Hare, A. E., Chung, W. K., Spiro, J. E., Faucett, W. A., Martin, C. L., & Ledbetter, D. H.
Affiliations
  • 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
  • Bucknell University (US)
  • Boston Children's Hospital (US)
  • University of Washington (US)
  • Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • Geisinger Medical Center (US)
  • Department of Psychiatry, Yale University, New Haven, Connecticut
  • Autism & Developmental Medicine Institute (US)
  • Simons Foundation (US)
Corresponding author
Ledbetter, David H.
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2015-02-01
Volume
72
Issue
2
Pages
119
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2014.2147
OpenAlex
W2053904865
Cited by
137
References
37
Citations by year
2026: 3 · 2025: 11 · 2024: 8 · 2023: 3 · 2022: 11 · 2021: 22 · 2020: 13 · 2019: 13 · 2018: 11 · 2017: 16 · 2016: 12 · 2015: 13 · 2014: 1
FWCI
9.17
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Bucknell Digital Commons (Bucknell University) (submittedVersion)
Funders
National Institute of Mental Health (5T32MH19961-14, R01MH074090, T32MH019961, R25MH071584)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
Keywords
copy number variation, de novo mutations, phenotypic variability, incomplete penetrance, variable expressivity, family background, cognitive ability, social behavior, neuromotor performance, body mass index, neurodevelopmental disorders, effect size, intraclass correlation coefficient
MeSH terms
Adult, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 16, Female, Humans, Intelligence, Male, Intellectual Disability, Parents, Phenotype, Psychomotor Performance, Social Behavior, Chromosome Disorders, Siblings, DNA Copy Number Variations

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