16p11.2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort
Abstract
Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication—the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo‐ versus hyperreflexia and macro‐ versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically‐caused neurodevelopmental disorders, clinicians should be aware of the more striking features—such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples—when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders. © 2016 Wiley Periodicals, Inc.
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Epilepsy/seizures ranks among the most common phenotypes observed in both 16p11.2 deletions and duplications.
“Epilepsy/seizures ranks among the most common phenotypes observed in both 16p11.2 deletions and duplications [10, 12, 16, 17, 33, 36] (Table 2).”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [36]
In studies with at least 50 subjects, 60-76% of 16p11.2 deletions were reported as de novo, while only 16-29% of 16p11.2 duplications occurred de novo.
“In studies with at least 50 subjects, between 60–76% of 16p11.2 deletions were reported as de novo events [10, 12, 34, 36], while only 16–29% of 16p11.2 duplications occurred de novo [10, 19, 34, 36].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [36]
16p11.2 duplications are similarly associated with speech articulation abnormalities, speech delay, and language deficits.
“Duplications are similarly associated with speech articulation abnormalities [36], speech delay [17, 19], and language deficits [16].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [36]
Speech articulation abnormalities, phonological processing disorder, language or communication disorder, speech or language deficits, and speech delay are present at high rates in 16p11.2 deletion carriers.
“Speech articulation abnormalities [36], phonological processing disorder [21, 23], language or communication disorder [14, 21, 23], speech or language deficits [15, 16], and speech delay [17, 33] are present at high rates in deletion carriers.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [36]
Macrocephaly is observed in subjects with the 16p11.2 microdeletion, whereas carriers of the duplication show microcephaly.
“Macrocephaly is observed in subjects with the 16p11.2 microdeletion, whereas carriers of the duplication show microcephaly [227, 292, 326, 337].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [337]
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- Authors
- Steinman, K. J., Spence, S. J., Ramocki, M. B., Proud, M. B., Kessler, S. K., Marco, E. J., Green Snyder, L., D'Angelo, D., Chen, Q., Chung, W. K., Sherr, E. H., & on behalf of the Simons VIP Consortium
- Affiliations
- University of Washington (US)
- Boston Children's Hospital (US)
- University Otolaryngology Providence Rhode Island
- Baylor College of Medicine (US)
- Children's Hospital of Philadelphia (US)
- University of California, San Francisco (US)
- Clinical Research Associates New York New York
- Mailman School of Public Health Columbia University New York New York
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Steinman, Kyle J.
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2016-07-13
- Volume
- 170
- Issue
- 11
- Pages
- 2943-2955
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- OpenAlex
- W2467348070
- Cited by
- 218
- References
- 43
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 22 · 2023: 20 · 2022: 14 · 2021: 29 · 2020: 19 · 2019: 19 · 2018: 55 · 2017: 14 · 2016: 1
- FWCI
- 23.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Simons Foundation Autism Research Initiative (SFARI) (198677)
- 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 › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- 16p11.2 deletion, 16p11.2 duplication, copy number variation, neurologic phenotype, autism spectrum disorder, neurodevelopmental disorders, hypotonia, hyporeflexia, hyperreflexia, action tremor, macrocephaly, microcephaly, seizures, Chiari I malformation, sacral dimple, corpus callosum abnormalities, ventriculomegaly, intellectual disability, developmental delay
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Electroencephalography, Epilepsy, Female, Genotype, Humans, Infant, Male, Middle Aged, Phenotype, Cohort Studies, Chromosome Disorders, Young Adult, Chromosome Duplication
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