Elsevier

Biological Psychiatry

Volume 77, Issue 9, 1 May 2015, Pages 785-793
Biological Psychiatry

Archival Report
The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population

https://doi.org/10.1016/j.biopsych.2014.04.021Get rights and content

Abstract

Background

Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes.

Methods

To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis.

Results

Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language–related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average.

Conclusions

Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.

Section snippets

Subjects

Subjects included individuals with the same recurrent 600 kb BP4-BP5 16p11.2 deletion without other pathogenic CNVs or known genetic diagnoses, the biological siblings of the individual with the deletion, and the biological parents of the individual with the deletion (Table 1). Siblings were selected for participation based on closeness in age to the carrier. One half-sibling was included. Adoptive parents were not used as control subjects but were interviewed for information about their

Psychiatric Diagnoses

Individuals with the 16p11.2 deletion presented with multiple psychiatric comorbid disorders (Figures S1 and S2 in Supplement 1): 93% of carriers had at least one diagnosis compared with only 21% of control subjects. Developmental coordination disorder, phonological processing disorder, language disorders, and ASD were the most common psychiatric diagnoses observed in carrier participants. Overall, there was a profile of speech and language–based disorders among the 16p11.2 deletion carriers,

Discussion

We performed detailed diagnostic, cognitive, and behavioral testing, including standardized ASD assessment, on individuals who were ascertained after clinical identification of the 16p11.2 deletion and family member cascade testing and compared them with familial control subjects. Our protocol addressed challenges in prior studies by way of standardization and comprehensive phenotyping. Our analyses clearly indicate that individuals with the deletion have a high frequency and range of

Acknowledgments and Disclosures

This work was supported by two grants from the Simons Foundation (Simons Foundation Autism Research Initiative Grant No. 198677 to EH, RB, RPG-K, and WKC and Simons Foundation Autism Research Initiative Grant No. 312100 to CLM, and DHL) and a grant from the National Institutes of Health (Grant No. MH074090 to DHL and CLM).

We thank all of the families at the participating Simons Variation in Individuals Project (Simons VIP) sites as well as the Simons VIP working group (Simons VIP consortium,

References (58)

  • H. Stefansson et al.

    CNVs conferring risk of autism or schizophrenia affect cognition in controls

    Nature

    (2014)
  • E. Hanson et al.

    Cognitive and behavioral characterization of 16p11.2 deletion syndrome

    J Dev Behav Pediatr

    (2010)
  • L.A. Weiss et al.

    Association between microdeletion and microduplication at 16p11.2 and autism

    N Engl J Med

    (2008)
  • F. Zufferey et al.

    A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

    J Med Genet

    (2012)
  • D.T. Miller et al.

    16p11.2 microdeletion

  • H.C. Mefford et al.

    Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

    N Engl J Med

    (2008)
  • S. Jamain et al.

    Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

    Nat Genet

    (2003)
  • B.S. Abrahams et al.

    Advances in autism genetics: On the threshold of a new neurobiology

    Nat Rev Genet

    (2008)
  • B. Wisniowiecka-Kowalnik et al.

    Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay

    Am J Med Genet B Neuropsychiatr Genet

    (2010)
  • S. Berkel et al.

    Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation

    Nat Genet

    (2010)
  • R.L. Milne et al.

    The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: An example from the Breast Cancer Family Registry

    Int J Epidemiol

    (2011)
  • S.J. Donovan et al.

    Commentary: Advent of sibling designs

    Int J Epidemiol

    (2011)
  • C.R. Weinberg et al.

    Choosing a retrospective design to assess joint genetic and environmental contributions to risk

    Am J Epidemiol

    (2000)
  • W.J. Gauderman et al.

    Family-based association studies

    J Natl Cancer Inst Monogr

    (1999)
  • Simons Variation in Individuals Project (Simons VIP): A genetics-first approach to studying autism spectrum and related neurodevelopmental disorders

    Neuron

    (2012)
  • J.G. Wishart et al.

    Instability of performance on cognitive tests in infants and young children with Down’s syndrome

    Br J Educ Psychol

    (1990)
  • R.C. Pianta et al.

    Relation between depressive symptoms and stressful life events in a sample of disadvantaged mothers

    J Consult Clin Psychol

    (1994)
  • D.W. Fulker et al.

    Genetic influence on general mental ability increases between infancy and middle childhood

    Nature

    (1988)
  • J. Sattler

    Assessment of Children: Cognitive Applications

    (2001)
  • Cited by (0)

    View full text