Psychiatric Syndromes in Individuals with Chromosome 18 Abnormalities

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 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 disorders *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

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 side of the points of the missing sections on the chromosome were also deletion breakpoint. These breakpoints are shown numerically in determined and documented for the 18q deletion subjects and two Tables I and II by subject and illustrated on a chromosome 18 of the 18p deletion subjects. ideogram per subject in Figure 2 (Table III). Subjects were interviewed by psychiatrists who themselves were Individually, the subjects in this study had a wide variety of blind to the specific chromosomal abnormality of the subject, any DSMIV diagnoses (as described in Tables IV–VI). We observed medical records or results of physical evaluations. The Diagnostic seven main types of psychiatric syndromes in our sample: Attention Interview for Genetic Studies (DIGS) [Nurnberger et al., 1994] was Deficit Disorders, Anxiety Disorders, Mood Disorders, Psychotic administered to subjects who were 18 years or older to assess for any Disorders, Stereotypic Movement Disorders, Learning Disorders, psychiatric disorders. The Schedule for Affective Disorders and and Communication Disorders. Rates of these various disorders Schizophrenia for School Aged Children-Present and Lifetime varied between type of subject (18q-, 18p-, 18p tetrasomy). 18q- Version (K-SADS-PL) [Kaufman et al., 1997] was administered subjects displayed high rates (>10% of subjects) of ADHD (41.7%), to subjects under 18 years old along with a parent. The Family anxiety disorders (58.3%), mood disorders (58.3%), psychotic Interview for Genetic Studies (FIGS) [Maxwell, 1992] was also disorders (16.7%), stereotypic movement disorders (15.4%), learn- administered to a family member close to the subject to assess for ing disorders (41.7%), and communication disorders (33.3%). any psychiatric disorders/symptoms not endorsed by the subject. A 18p- subjects displayed high rates of ADHD (66.6%), anxiety consensus best estimation diagnostic process was employed to disorders (66.7%), stereotypic movement disorders (33.3%), learn- determine psychiatric disorders. This entailed two other psychia- ing disorders (33.3%), and communication disorders (33.3%). 18p trists reviewing the DIGS or K-SADS-PL, the FIGS, and any medical tetrasomy subjects displayed high rates of ADHD (62.5%), anxiety ZAVALA ET AL. 839

TABLE I. 18p Deletion Subjects and Their Syndromes

Age at Proximal Distal Stereotypic Subject interview breakpoint breakpoint Depressive Manic Psychotic Anxiety movement Deletion ID (years) Gender region region syndrome syndrome syndrome syndrome disorder 18p- 18p-13C 18 F 1 14,905,715–14,908,354 þ 18p- 18p-10C 18 F 1 15,315,187–15,315,128 þ 18p- 18p-5C 16 F No data No data þ

disorders (37.5%), mood disorders (12.5%), psychotic disorders Given previous reports of genes for bipolar disorder and schizo- (12.5%), stereotypic movement disorders (88.9%), and commu- phrenia being present on chromosome 18, we broke subjects’ nication disorders (50%). All three types of subjects showed high psychiatric pathology into four types of syndromes (anxious, rates (>10%) of anxiety disorders (58.3% of 18q-, 66.7% of 18p-, depressed, manic, and psychotic). Subjects could have one or more 37.5% of 18p tetrasomy), communication disorders (33.3% of 18q-, syndrome. Anxiety disorder NOS, speciﬁc phobia, generalized 33.3% of 18p-, 50% of 18p tetrasomy), and motor skills disorders anxiety disorder, separation anxiety disorder, social phobia, obses- (38.5% of 18q-, 33.3% of 18p-, 33.3% of 18p tetrasomy). Stereo- sive compulsive disorder were categorized as anxiety syndromes. typic movement disorder was diagnosed in 88.9% of 18p tetrasomy Depressive disorder NOS, major depressive episodes, premenstrual subjects, 33.3% of the 18p- deletion subjects, and 15.4% of the18q- dysphoric disorder, and major depressive disorder were categorized deletion subjects. as depressive syndromes. Bipolar disorder, bipolar disorder NOS,

TABLE II. 18q Deletion Subjects and Their Syndromes

Age at Proximal Distal Stereotypic Subject interview breakpoint breakpoint Depressive Manic Psychotic Anxiety movement Deletion ID (years) Gender region region syndromes syndromes syndromes syndromes disorder 18q- 18q-71M 32 F 70,762,884– 76,117,153 þþþ 70,770,748 18q- 18q-155C 14 M 64,808,770– 71,606,198– þþ 64,816,108 71,626,363 18q- 18q-33C 12 F 65,057,388– 76,117,153 þþþ 65,082,480 18q- 18q-162C 21 M 64,635,628– 76,117,153 þþþ 64,640,012 18q- 18q-83C 20 F 61,765,591– 76,117,153 þþ 61,788,547 18q- 18q-43C 11 M 60,006,132– 76,117,153 þþ 60,036,967 18q- 18q-96C 18 M 59,063,616– 76,117,153 þ 59,072,231 18q- 18q-42C 13 F 58,558,562– 76,117,153 58,581,153 18q- 18q-2C 13 F 57,367,714– 76,117,153 þþþ 57,373,741 18q- 18q-154C 17 (months) F 56,688,040– 76,117,153 56,699,873 18q- 18q-6C 15 F 56,190,032– 76,117,153 No data No data No data No data No data 56,218,651 18q- 18q-69C 12 M 54,720,747– 76,117,153 54,736,162 18q- 18q-67C 7 F 53,556,003– 76,117,153 þ 53,586,273 18q- 18q-58C 13 F 51,181,396– 76,117,153 þþ 51,199,374 840 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

TABLE III. Tetrasomy 18p Subjects and Their Syndromes

Age at Stereotypic Subject interview Depressive Manic Psychotic Anxiety movement Abnormality ID (years) Gender syndrome syndrome syndrome syndrome disorder Tet18p Tet18p2C 18 F þ Tet18p Tet18p8C 12 M þþ Tet18p Tet18p9C 7 M þþ Tet18p Tet18p13C 20 F þþ Tet18p Tet18p26C 3 F þ Tet18p Tet18p27C 20 (months) M Tet18p Tet18p24C 7 F þþ Tet18p Tet18p10C 4 F þþ Tet18p Tet18p3C 8 F þ

manic episodes, and substance induced mood disorder with manic for bipolar disorder and schizophrenia tends to be in the 20s for features were categorized as manic syndromes. Psychotic disorder bipolar disorder [Hirschfeld et al., 2000] and in thelate teens to early NOS, bipolar disorder severe with psychotic features, and major 20s for schizophrenia [Hafner et al., 1994]. depressive episode severe with psychotic features were categorized The current study is hopefully of interest to physicians, mental as psychotic syndromes. Lifetime rates of these syndromes, plus health professionals, and family members who interact with per- rates of stereotypic movement disorder are shown in Figure 1. sons who have chromosome 18 abnormalities as well as to persons Of the chromosome 18q- deletion subjects, 58.3% had a depres- working to identify the location of genes which predispose to sive syndrome, 58.3% had an anxiety syndrome, 25% had a manic psychiatric disorders which may be located on chromosome 18. syndrome, and 25% had a psychotic syndrome. Of the chromosome Although there were some commonalities across the three types of 18p- deletion subjects, 66.6% had an anxiety syndrome, and none chromosome 18 disorder studied here (i.e., anxiety disorders were had depressive, manic, or psychotic syndromes. Of the chromo- present in all three types), we did find particular phenotypes some 18p tetrasomy subjects, 50% had an anxiety syndrome, 12.5% associated with the chromosomal disorders. had a psychotic syndrome, and no mood syndromes were present. Anxiety disorders were seen in 58.3% of 18q- deletion subjects, Two subjects were too young to carry a diagnosis and one subject 66.6% of 18p- subjects, and 50% of tetrasomy subjects. The range of had no psychiatric evaluation done, thus, they were left out of these expression of anxiety syndromes varied from generalized anxiety to percentages (Fig. 1). specific phobias and obsessive compulsive disorder. These rates of Since a significant number of the subjects studied here were also anxiety disorder are quite elevated compared to general epidemio- young children, it is important to realize that our estimates of the logic studies which estimate about 28.8% lifetime prevalence percentages of subjects with psychiatric pathology are likely to be [Kessler and Wang, 2008]. As anxiety disorders can be quite low estimates of what might be seen if all subjects were studied in disabling and can prevent adaptation to school, work, and relation- adulthood. Particular syndromes, such as mania and psychosis, are ships [Markowitz et al., 1989; Kessler and Frank, 1997], it therefore challenging to diagnose in children, and moreover, the typical onset behooves physicians treating persons with these chromosomal

TABLE IV. DSMIV Axis I Diagnoses of Chromosome 18p- Subjects

Type of disorder DSMIV diagnosis No. of affected/no. of assessed Attention deficit and disruptive behavior disorders Attention deficit hyperactivity disorder 2/3 Anxiety disorders Anxiety disorder not otherwise specified 1/3 Obsessive compulsive disorder 1/3 Motor skills disorders Developmental coordination disorder 1/3 Communication disorders Expressive language disorder 1/3 Learning disorders Reading disorder 1/3 Mathematics disorder 1/3 Other disorders of infancy, childhood, or adolescence Stereotypic movement disorder 1/3 ZAVALA ET AL. 841

TABLE V. DSM IV Axis I Diagnoses of Chromosome 18q- Subjects

No. of affected/no. Type of disorder DSMIV diagnosis of assesseda Attention deficit and disruptive behavior disorders Attention deficit hyperactivity disorder 5/12 Disruptive behavior disorder not otherwise specified 1/12 Anxiety disorders Anxiety disorder not otherwise specified 2/12 Specific phobia 3/12 Generalized anxiety disorder 2/12 Social phobia 1/12 Depressive disorders Depressive disorder not otherwise specified 4/12 Major depressive disorder 3/12 Bipolar disorders Bipolar I disorder 1/12 Bipolar disorder not otherwise specified 1/12 Mood disorder not otherwise specified 1/12 Other Disorders of Infancy, childhood, or adolescence Stereotypic movement disorder 2/13 Separation anxiety disorder 2/12 Pervasive developmental disorders Pervasive developmental disorder not otherwise specified 2/13 Motor skills disorders Developmental coordination disorder 5/13 Feeding and eating disorders of infancy or Early Childhood Feeding disorder of infancy or early childhood 1/13 Impulse control disorders not elsewhere classified Trichotillomania 1/12 Elimination disorders Enuresis 2/12 Encopresis 1/12 Learning disorders Learning disorder not otherwise specified 4/12 Reading disorder 1/12 Disorder of written expression 1/12 Communication disorders Expressive language disorder 4/12 Schizophrenia and other psychotic disorders Psychotic disorder NOS 2/12 Primary sleep disorders Sleep terror disorder 1/12 Substance-related disorders Substance induced mood disorder with manic features 1/12 Alcohol dependence 1/12 Relational problems Parent-child relational problem 1/12

aNote that total number of subjects was 13, however, one subject was 17 months old, thus was left out of no. of assessed in disorders that this subject was too young to be diagnosed with.

abnormalities to incorporate a screen for anxiety disorders and to recurrent major depression and anxiety, with a LOD score of assist patients and families in finding adequate therapies for these 3.75, on chromosome 18q21.33-18q22.2 [Camp et al., 2005]. One disorders. gene of interest in this segment of chromosome 18 is GALR1, which In addition to high rates of ADHD and anxiety, the 18q- subjects has been associated with depression and anxiety disorders in rodent (with distal breaks beginning from 18q21.2 through 18q22.3) models [Karlsson and Holmes, 2006]. Given our findings, we would exhibited high rates of mania, depression, and psychosis. Rates of recommend that persons with 18q- deletions be screened for psychosis were 24 times higher than the general population rate psychosis, depression, and mania, in addition to anxiety disorders. [Kick, 2001]. Rates of mania were 6–8 times higher, and rates of The psychiatric syndromes associated with 18p tetrasomy were, depression were 3.5 times higher than that seen in the general by contrast, primarily stereotypies, anxiety disorders, and psycho- population [Kessler and Wang, 2008]. These findings suggest that sis, all at rates several times that seen in the general population, but haplo-insufficiency (loss of one copy of a gene or genes) on 18q22- we found no evidence of mood disorders (mania or depression). 23 may underlie the expression of some forms of psychosis, mania, The stereotyped movement disorders, found in most of these and depression. Several other studies have suggested that the 18q21- subjects, are of special interest, given reports of potential genes 23 region harbors genes which predispose to bipolar disorder [Stine associated with various dystonic syndromes associated with chro- et al., 1995; Freimer et al., 1996; McInnis et al., 2003; Schulze et al., mosome 18p [Tezzon et al., 1998; Awaad et al., 1999; Klein et al., 2003] or psychosis [Walss-Bass et al., 2005], and the MYO5B gene, 1999; Han et al., 2007]. In regard to these subjects, it is interesting to on 18q21, was recently highlighted in a genome wide association note that the 18p arms are duplicated, as opposed to the other analysis of bipolar disorder [Sklar et al., 2008]. Given the high subjects where deletions of segments occur. percentage of 18q- subjects with anxiety and/or depression, it is also Despite the fact that several studies have identified potential of interest that a recent genome screen identified a locus for loci [Bassett, 1992; McInnes et al., 1996; Escamilla et al., 2001; 842 AMERICAN JOURNAL OF MEDICAL GENETICS PART B

TABLE VI. DSM IV Axis I Diagnoses of Chromosome 18p Tetrasomy Subjects

No. of affected/no. Type of disorder DSMIV diagnosis of assesseda Attention deficit and disruptive behavior disorders Attention deficit hyperactivity disorder 5/8 Oppositional defiant disorder 1/8 Anxiety disorders Anxiety disorder not otherwise specified 1/8 Specific phobia 1/8 Generalized anxiety disorder 1/8 Other disorders of infancy, childhood, or adolescence Stereotypic movement disorder 8/9 Separation anxiety disorder 1/8 Pervasive developmental disorders Pervasive developmental disorder not otherwise specified 3/9 Motor skills disorders Developmental coordination disorder 3/9 Elimination disorders Enuresis 4/8 Encopresis 2/8 Communication disorders Expressive language disorder 4/8 Impulse control disorders not elsewhere classified Impulse control disorder not otherwise specified 1/8 Schizophrenia and other psychotic disorders Psychotic disorder NOS 1/8 Primary sleep disorders Primary insomnia 1/8 Bipolar disorders Mood disorder not otherwise specified 1/8

aNote that total number of subjects was nine, however, one subject was 20 months old, thus was left out of no. of assessed in disorders that this subject was too young to be diagnosed with.

Mukherjee et al., 2006] and candidate genes (TGIF [Chavarrıa-Siles chromosome 18p and at least one previous report of psychosis in et al., 2007], NDUFV2 [Wasizuka et al., 2009], VAPA [Lohoff et al., a subject with an 18p- deletion [Babovic-Vuksanovic et al., 2004]. 2008], NAPG [Weller et al., 2006], IMPA2 [Yoshikawa et al., 2001; This study focused on psychiatric manifestations of persons with Sjøholt et al., 2004], GNAL [Tsiouris et al., 1996]) related to karyotypic anomalies of chromosome 18. This type of case report is schizophrenia and bipolar disorder as being on chromosome unique in that we systematically assessed 25 subjects afﬂicted with 18p, the three 18p- subjects here showed no evidence of psychotic these conditions and matched speciﬁc deletions with psychiatric or affective pathology. Nevertheless, given the small sample size of syndromes. Although the current study allows us to look at persons 18p- subjects here, we recommend screening for psychosis and with karyotipically evident chromosomal deletions/duplications, bipolar disorder, in addition to ADHD and anxiety disorders, given newer technologies also allow for detection of smaller deletions and the above mentioned reports of linkage for these disorders to copy number variants (CNV). CNV analyses [Beckmann et al.,

FIG. 1. Chromosome 18 abnormalities and their incidence of syndromes. ZAVALA ET AL. 843

FIG. 2. Deleted segments of chromosome 18 by subject.

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