Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders
- D T Miller1,2,3,4,
- Y Shen1,3,4,5,
- L A Weiss3,4,5,6,
- J Korn5,6,
- I Anselm3,7,
- C Bridgemohan3,8,
- G F Cox2,3,9,
- H Dickinson10,
- J Gentile2,3,11,
- D J Harris2,3,
- V Hegde2,3,
- R Hundley3,8,
- O Khwaja3,4,7,
- S Kothare3,7,12,
- C Luedke3,13,
- R Nasir3,4,8,
- A Poduri3,7,
- K Prasad3,7,
- P Raffalli3,7,
- A Reinhard1,2,
- S E Smith2,3,9,
- M M Sobeih3,4,7,
- J S Soul3,7,
- J Stoler2,3,
- M Takeoka3,7,12,
- W-H Tan2,3,
- J Thakuria2,3,
- R Wolff3,7,
- R Yusupov2,3,
- J F Gusella3,4,5,6,
- M J Daly3,4,5,6,
- B-L Wu1,3,4
- 1Department of Laboratory Medicine, Children’s Hospital Boston, Boston, Massachusetts, USA
- 2Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, USA
- 3Harvard Medical School, Boston, Massachusetts, USA
- 4Autism Consortium, Boston, Massachusetts, USA
- 5Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
- 6The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- 7Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, USA
- 8Division of Developmental Medicine, Children’s Hospital Boston, Boston, Massachusetts, USA
- 9Genzyme Corporation, Cambridge, Massachusetts, USA
- 10Department of Otolaryngology and Communication Enhancement, Children’s Hospital Boston, Boston, Massachusetts, USA
- 11Department of Psychiatry, Children’s Hospital Boston, Boston, Massachusetts, USA
- 12Division of Epilepsy and Clinical Neurophysiology, Children’s Hospital Boston, Boston, Massachusetts, USA
- 13Division of Endocrinology, Children’s Hospital Boston, Boston, Massachusetts, USA
- Dr B-L Wu, Department of Laboratory Medicine, Children’s Hospital Boston, 300 Longwood Ave, Boston, Massachusetts 02115, USA; bai-lin.wu{at}childrens.harvard.edu
- Received 29 April 2008
- Revised 8 July 2008
- Accepted 1 August 2008
- Published Online First 19 September 2008
Abstract
Background: Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities.
Patients: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.
Results: We report the clinical features of five patients with a BP4–BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ~1.5 Mb (chr15:28.719–30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover ~500 kb (chr15:28.902–29.404 Mb) and contain three reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.
Conclusions: The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.
Footnotes
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‣ Additional material is published online only at http://jmg.bmj.com/content/vol46/issue4
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Funding: We acknowledge the following sources of financial support: Young Investigator Award from the Children’s Tumor Foundation (to YS). Ruth L Kirschstein National Research Service Award (to LAW); National Institutes of Health grant P01-GM061354, Autism Speaks, and NARSAD Distinguished Investigator Award (to JFG), Harvard Scholars in Clinical Science Program K30 grant RRO22292-07 (to JT), grants from the Autism Consortium and the Ellison Foundation (to MJD), and grants from the NIH-CETT Program and the MDA Foundation (to BLW).
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Competing interests: None declared.
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Patient consent: Obtained.
