title: 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.
authors.affiliation: University of Washington and Seattle Children's Research Institute, Seattle, Washington. kylejs@uw.edu.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Steinman
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Spence
authors.affiliation: University Otolaryngology, Providence, Rhode Island.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Ramocki
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: Monica B
authors.initials: MB
authors.lastname: Proud
authors.affiliation: Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Kessler
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Elysa J
authors.initials: EJ
authors.lastname: Marco
authors.affiliation: Clinical Research Associates, New York, New York.
authors.forename: LeeAnne
authors.initials: L
authors.lastname: Green Snyder
authors.affiliation: Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Debra
authors.initials: D
authors.lastname: D'Angelo
authors.affiliation: Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Qixuan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Columbia University Medical Center, New York, New York.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics*; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16; D015331:Cohort Studies; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
keywords: 16p11.2 deletion; 16p11.2 duplication; articulation disorders, developmental; associations, genotype-phenotype; copy number variants, DNA; epilepsy; hypotonia; incoordination; macrocephaly; manifestations, neurogical; microcephaly; sacral dimple; tremor