Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

• Published in: Journal of medical genetics Vol. 47; no. 5; pp. 332 - 341
• Main Authors: Shinawi, Marwan, Liu, Pengfei, Kang, Sung-Hae L, Shen, Joseph, Belmont, John W, Scott, Daryl A, Probst, Frank J, Craigen, William J, Graham, Brett H, Pursley, Amber, Clark, Gary, Lee, Jennifer, Proud, Monica, Stocco, Amber, Rodriguez, Diana L, Kozel, Beth A, Sparagana, Steven, Roeder, Elizabeth R, McGrew, Susan G, Kurczynski, Thaddeus W, Allison, Leslie J, Amato, Stephen, Savage, Sarah, Patel, Ankita, Stankiewicz, Pawel, Beaudet, Arthur L, Cheung, Sau Wai, Lupski, James R
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.05.2010; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Arrays; Artificial chromosomes; Attention Deficit Disorder with Hyperactivity - genetics; Autism; Autistic Disorder - genetics; Biological and medical sciences; Child; Child development; Child, Preschool; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; Cloning; Comparative Genomic Hybridization; copy number variations; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - pathology; Developmental delay; Developmental Disabilities - genetics; epilepsy; Epilepsy - genetics; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotype & phenotype; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Infant; Informed consent; Intellectual Disability - genetics; Labeling; Laboratories; Language Development Disorders - genetics; macrocephaly and microcephaly; Male; Medical genetics; Medical sciences; Microcephaly - genetics; Molecular and cellular biology; Nervous system (semeiology, syndromes); Neurology; Oligonucleotide Array Sequence Analysis; Patients; Phenotype; Segmental Duplications, Genomic; Young Adult; United States > US; California; Human; Nervous system diseases; Relapse; Head; Epilepsy; Size; Developmental disorder; Recurrent; Cerebral disorder; Behavioral disorder; Dysmorphism; Malformation; Central nervous system disease; Genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2009.073015

BackgroundDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.MethodWe indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.ResultsThe most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.ConclusionsRecurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.