BRIEF RESEARCH COMMUNICATION Neuropsychiatric Genetics Psychiatric Syndromes in Individuals With Chromosome 18 Abnormalities Juan Zavala,1 Mercedes Ramirez,1 Rolando Medina,1,2 Patricia Heard,3 Erika Carter,3 AnaLisa Crandall,3 Daniel Hale,3 Jannine Cody,3 and Michael Escamilla1,4,5* 1Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2Psychiatry Service, Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas 3Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 4Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 5South Texas Medical Genetics Research Group, Regional Academic Health Center, Edinburg, Texas Received 3 December 2008; Accepted 17 September 2009 Chromosome 18 abnormalities are associated with a range of physical abnormalities such as short stature and hearing impair- How to Cite this Article: ments. Psychiatric manifestations have also been observed. This Zavala J, Ramirez M, Medina R, Heard P, study focuses on the presentations of psychiatric syndromes as Carter E, Crandall A, Hale D, Cody J, they relate to specific chromosomal abnormalities of chromo- Escamilla M. 2010. Psychiatric Syndromes in some 18. Twenty-five subjects (13 with an 18q deletion, 9 with Individuals With Chromosome 18 18p tetrasomy, and 3 with an 18p deletion), were interviewed by Abnormalities. psychiatrists (blind to specific chromosomal abnormality) using Am J Med Genet Part B 153B:837–845. the DIGS (subjects 18 and older) or KSADS-PL (subjects under 18). A consensus best estimation diagnostic process was employed to determine psychiatric syndromes. Oligonucleotide Array Comparative Genomic Hybridization (Agilent Technologies) impairments [Jones, 2006; Linnankivi et al., 2006; Swingle et al., was utilized to define specific regions of chromosome 18 that 2006; Wester et al., 2006]. Although less systematically studied, were deleted or duplicated. These data were further analyzed to many subjects with chromosome 18 abnormalities also manifest determine critical regions of the chromosome as they relate to neuropsychiatric symptoms. Mental retardation is found in case phenotypic manifestations in these subjects. 58.3% of the chro- reports of all three abnormalities (18p-, 18q-, and 18p tetrasomy), mosome 18q- deletion subjects had depressive symptoms, 58.3% and in one study was estimated at 68% of all 18q deletion subjects had anxiety symptoms, 25% had manic symptoms, and 25% had [Semrud-Clikeman et al., 2005]. Abnormal EEG findings and psychotic symptoms. 66.6% of the chromosome 18p- deletion epilepsy have been described in case reports for all three chromo- subjects had anxiety symptoms, and none had depressive, manic, somal disorders [Chudley et al., 1974; Wilson et al., 1979; Wilson or psychotic symptoms. Fifty percent of the chromosome 18p and Al Saadi, 1989; Schinzel et al., 1991; Chudley et al., 1992; tetrasomy subjects had anxiety symptoms, 12.5% had psychotic Krasikov et al., 1992; Poissonnier et al., 1992; Engelen et al., 1998; symptoms, and 12.5% had a mood disorder. All three chromo- Tinkle et al., 2003; Linnankivi et al., 2006; Swingle et al., 2006; Brenk somal disorders were associated with high anxiety rates. et al., 2007; Cody et al., 2007]. Many subjects with 18p or 18q Psychotic, manic and depressive disorders were seen mostly in deletions display delayed speech, mutism, or articulation difficul- 18q- subjects and this may be helpful in narrowing regions for ties [Thompson et al., 1986; Poissonnier et al., 1992; Grosso et al., candidate genes for these psychiatric conditions. 1999; Babovic-Vuksanovic et al., 2004; Wester et al., 2006; Brenk Ó 2009 Wiley-Liss, Inc. et al., 2007; Cody et al., 2007] and there has been one report of short Key words: 18p; 18q; deletions; tetrasomy; psychiatric disor- ders *Correspondence to: Michael Escamilla, M.D., Department of Psychiatry, South Texas Psychiatric Genetics Research Center, University of Texas Health Chromosome 18 macro-deletions (detectable by standard Science Center at San Antonio, 454 Soledad, Suite 200, San Antonio, karyotyping), which may include deletions on either the 18q or TX 78205. E-mail: [email protected] 18p arm of the chromosome, have an estimated frequency of 1in Published online 19 November 2009 in Wiley InterScience 40,000 live births [Cody et al., 1999] and result in a wide range of (www.interscience.wiley.com) physical abnormalities ranging from short stature to hearing DOI 10.1002/ajmg.b.31047 Ó 2009 Wiley-Liss, Inc. 837 838 AMERICAN JOURNAL OF MEDICAL GENETICS PART B attention span in three out of three 18p- subjects [Thompson et al., or psychiatric records available at the time of review. A consensus 1986]. diagnosis was then determined by the reviewers for each subject. There have been a paucity of studies on psychiatric difficulties Formal diagnoses were assigned using criteria from the Diagnostic experienced by persons with chromosome 18 abnormalities, and and Statistic Manual for Psychiatric Disorders, Version 4 (DSMIV) only two studies [Mahr et al., 1996; Vermeulen et al., 2005] utilized [American Psychiatric Association, 1994]. In addition, the diag- systematic psychiatric scales. In studies of persons with chromosome nosticians used DSMIV criteria to define episodes of major depres- 18p- deletions, there have been reports of two persons with autism sion, mania, and psychosis, irrespective of the overall DSMIV [Ghaziuddin et al., 1993; Wester et al., 2006], and one person with diagnosis. Although it is possible that the chromosomal abnormal- paranoid psychosis, depression, and subclinical obsessive compul- ities are direct causes of the various psychiatric syndromes and sive disorder [Babovic-Vuksanovic et al., 2004]. In studies of 18q- disorders in these patients, as no psychiatric disorder has been syndromes, there havebeen individualreports ofautistic featuresin8 confirmed to be caused by these chromosomal abnormalities, we subjects [Wilson and Al Saadi, 1989; Schinzel et al., 1991; Poissonnier did not diagnose these patients as having diagnoses secondary to a et al., 1992; Mahr et al., 1996; Tinkle, 2003; Linnankivi et al., 2006], general medical condition. attention deficit and/or hyperactivity disorder in 6 subjects [Surh Array design: Custom-designed oligonucleotide arrays produced et al., 1991; Chudley et al., 1992; Mahr et al., 1996; McEntagart et al., by Agilent Technologies (Santa Clara, CA) were used to identify 2001; Tinkle, 2003; Cody et al., 2007], and violent/aggressive behav- breakpoints. The assays used in this study allowed for resolution of iors have been reported in 14 subjects [Chudley et al., 1974; Wilson 32,000 regions across chromosome 18 and 12,000 across the and Al Saadi, 1989; Poissonnier et al., 1992; Mahr et al., 1996; remainder of the genome. This allowed us to generate very high- McEntagart et al., 2001; Tinkle, 2003]. There is only one report of resolution breakpoint data for the individuals in our study who a behavioral/psychiatric problem in a case of chromosome 18p have karyotypically diagnosed deletions of chromosome 18. It also tetrasomy; an individual who had a history of aggressive, self- allowed us to rule out other large genomic imbalances in the rest of injurious, and destructive behavior [Swingle et al., 2006]. There is the genome. onereportofa familywitha pericentricinversion ofchromosome 18, Array Hybridization and Analysis: The hybridization was per- in which three individuals (two with dup(18p)/del(18q) and one formed as described in the Agilent protocol. Comparative Genomic with dup(18q)/del(18p)) all displayed depression and anxiety, as Hybridization (CGH) uses a two-sample comparative method in measured by standardized instruments [Vermeulen et al., 2005]. which the test (or patient) sampled is assessed in comparison to a In this present study, we attempted to categorize and delineate reference sample. The two DNA samples are labeled with different psychiatric disorders and syndromes associated with chromosome fluorophores, then mixed together, and allowed to competitively 18q-, chromosome 18p- and 18p tetrasomy subjects, using blinded hybridize to the oligonucleotides on the array slide. The reference psychiatric assessments, standardized diagnostic instruments, and DNA samples are from Promega (Madison, WI) and consist of a consensus diagnostic process. pooled same sex DNA samples. No second confirmatory dye swap Twenty-five subjects were recruited from the Chromosome 18 experiment was performed because each study participant had a Registry & Research Society. The subjects in this registry were previous diagnosis of a chromosome 18 deletion. Each array was known to have an abnormality of chromosome 18 defined by scanned using the Agilent laser scanner, the scan data were extracted standard karyotyping. Thirteen subjects were identified as having using Agilent Feature Extraction (version 8.1.1) and those data were 18q deletions, nine subjects had 18p tetrasomy, and three had 18p analyzed using the CGH Analytics software. Data points were deletions, all diagnosed by karyotyping. Written informed consent analyzed in continuous pairs and log 2 ratios of sample DNA was was obtained for all procedures and an institutional review board compared to control DNA. Breakpoints were determined to be approved protocol was followed. Molecular analysis of the break- between the base-pair ends for the features on either