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In addition to chromosomal regions implicated by linkage analysis, some chromosomal regions have also been implicated in the development of these disorders based on chromosomal abnormalities such as deletions, translocations and trisomies.

There are few reports of chromosomal abnormalities associated with major psychiatric disorders (Bassett, 1992; Craddock and Owen, 1994, De Lisi et al., 1994). It is speculated that this is likely due to the fact that geneticists usually consult on paediatric cases and seldom follow up into adolescence or adulthood, when many psychiatric disorders first appear. It would also appear that psychiatrists generally do not suspect genetic syndromes in psychiatric patients as a first cause (Bassett et al., 2000).

Despite this, some researchers have provided compelling evidence for increased prevalence of a number of psychiatric illness among patients suffering from syndromes caused by chromosomal abnormalities.

Furthermore, there are numerous examples of diverse conditions where a chromosomal aberration has led the way to the identification of possible susceptibility loci (Castermans et al., 2004). The section that follows will deal with these chromosomal abnormalities, how they provide a possible means to help localise causative genes and the roles they play in our understanding of the genetic complexity of mental illness.

1.4.5.1. Chromosome 22q11 deletion syndrome

Chromosome 22 deletion syndrome (22qDS) is the second most common genetic syndrome after Down Syndrome (Gothelf and Lambroso, 2001) that affects approximately one in 4000 individuals worldwide (du Montcel et al., 1996). The syndrome encompasses velocardiofacial syndrome (VFCS), DiGeorge syndrome and conotruncal anomaly face syndrome (CTAFS), all due to chr22q11.2 microdeletions (Fig 1.7) (Demczuk and Aurias et al., 1995), which generally occur de novo (Demczuk and Aurias et al , 1995; Leana-Cox et al., 1994). Learning disabilities, palatal anomalies, cardiac defects and atypical facial features are common, although the presentation is highly variable (Yamagisgi et al., 1999). It is inferred that the symptoms

Comment [IT46]: 1.Du Montcel ST, Mendizabal H, Ayme S, Levy A, Philip N, 1996.

Prevalence of 22q11 microdeletions of 22q11.2 in velo-cardio-facial syndrome. J Med Genet 44: 261-68

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associated with the deletions, which vary in extent in different patients, are associated with the loss of particular genes harboured in the missing region. Most interestingly, a review of 22qDS found that psychiatric disorders, of which schizophrenia was the most frequent, were reported in 53% of cases of 22qDS that were not ascertained from psychiatric sources (Papolos et al., 1996; Pulver et al., 1994). Studies have also shown an increased rate of 22qDS among schizophrenia patients. These studies used fluorescence in situ hybridization (FISH) and a chr22q11.2 probe to demonstrate that approximately 2% of patients with schizophrenia have the chr22q11.2 microdeletion, compared to 0.0025% in the general population.

The findings above lend support to the likelihood that a meaningful association exists between this chromosomal anomaly and schizophrenia (Propping et al., 1995; Karayiorgou et al., 1996; Bassett et al., 1999). There have been some positive linkage data to markers on chr22q11.2 (section 1.4.3.9), but most linkage findings have tended to cluster around a 4-5 cM region around 22q13, approximately 25Mb telomeric to chr22q11.2. This could suggest that there may be two or more loci on chromosome 22 involved in schizophrenia (Schwab et al., 1999) (Fig 1.7).

Obsessive-compulsive symptoms have also been observed in a number of 22qDS patients (Karayiorgou et al., 1997, Pulver et al., 1994). A follow up study by Papolos and colleagues on behavioural phenotypes of patients with 22qDS observed a high rate of OCS in many of these patients (Papolos et al., 1994). In fact, Gothelf and colleagues noted that, in their clinical experience, not only did many of their VCFS patients suffer from OCS, but the family members of many of these patients reported that the OCS were the most disruptive behavioural symptoms of the patient (Gothelf et al., 2004). Three investigations reported rates of OCS and OCD in VCFS patients of 14% (Pulver et al., 1994), 8% (Papolos et al., 1996) and 12% (Feinstein et al., 2002). These findings provide strong evidence that genes involved in increased OCD susceptibility may be harboured at the chr22q11 region.

1.4.5.2. Other chromosomal aberrations

A balanced (1;11)(q42;q14.3) reciprocal translocation has been found to co-segregate with schizophrenia in a large Scottish family (Millar et al., 2000; Blackwood et al., 2001; St Clair et al., 1990). In a linkage study of schizophrenia in this family, the translocation generated a LOD score of 3.6 when the phenotype was restricted to schizophrenia. The LOD score increased to 7.0 when the disease definition was expanded to include major depression and bipolar disorder (Blackwood et al., 2001). Furthermore, the Disrupted in Schizophrenia (DISC) genes (Sawamura and Sawa, 2006), DISC1 and DISC2, are disrupted by this translocation that segregates within the family (Blackwood et al., 2001). Interestingly, in an earlier study by Ekelund and colleagues, the strongest evidence for linkage in their combined sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene (Ekelund et al., 2001) (Table 1.4)

In their cytogenetic analysis of an extended pedigree, Calzolari and colleagues identified two individuals carrying a balanced translocation with a breakpoint at chr15q13-14. One was diagnosed with psychotic disorder at 15 years of age, while the other was diagnosed with schizoaffective disorder at 16 years of age,

Comment [MB47]: Sawamura N, Sawa A.

Disrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major

mental illnesses.

Ann N Y Acad Sci. 2006 Nov;1086:126-33.

51 neither of these two disorders were otherwise present within the pedigree (Calzolari et al., 1996). Other genetic illnesses linked to chr15q have been reported to co-express psychosis resembling schizophrenia, namely Prader-Willi syndrome, a disease involving imprinting of genes at chr15q11-12 (Clarke, 1993), Marfan syndrome, which generally involves mutations of the fibrillin gene at chr15q21 (Sirota et al., 1990) and Andersmann’s angenesis of the corpus collosum, which is caused by a deletion of chr15q (Casaubon et al., 1996).

Translocations have also been utilised to identify possible OCD susceptibility loci in various studies.

However, many of these studies make use of a wide phenotypic definition, viz., TS/OCD/chronic tic disorder (CTD) phenotypic spectrum (Cuker et al., 2004) (section 1.2.1).

Three cases of this TS/OCD/CTD spectrum phenotype associated with translocations have previously been reported. In 1996, Boghosian-Sell and co-workers reported a familial form of TS associated with obsessive-compulsive sympoms that segregated with a balanced t(7;18)(q22-q31; q22.3) translocation (Boghosian-Sell et al., 1996). Subsequently, State and colleagues reported on a young man with CTD and OCD, who was found to carry a paracentric inversion i(18q21.1-q22.2) (State et al., 2003). These investigators mapped the telomeric end of the inversion to a genomic location that is less than 1Mb from the translocation described by Boghsian-Sell and others (1996) (State et al., 2003). More recently, Cuker and others described a 14 year-old girl with a t(2,18)(p12;q22) translocation with severe OCD (Cuker et al., 2004). Fine mapping of the patient’s chr18 breakpoint revealed it to be within 4.7Mb of the previously reported breakpoint (Bogh-Sell et al., 1996); thus these studies implicate a locus on chr18q in the development of OCD.

Moreover, two chromosomal breakpoints associated with TS/OCD/CTD has been shown to disrupt particular genes. Petek and co-workers described a 13-year-old boy with a de novo duplication of a region of chr7 [dup (7)(q22.1-q31.1)] who developed TS/OCD/CTD without any signs of overt mental retardation. These researchers further showed that this duplication was inverted and disrupted IMMP2L, the human homologue to the yeast mitochondrial inner membrane peptidase subunit 2 (Petek et al., 2001). Whether it is this gene that plays a role in OCD or whether inversion of, or the presence of, genes on the duplicated region are involved, has not yet been investigated (Cuker et al., 2004).

In another study, the contactin-associated protein (CNTNAP2) gene (CNTCAP2) was found to be disrupted in a TS/OCD/CTD family with a complex translocation involving chr2 and chr7 (Verkerk et al., 2003). Three of the family members investigated (a father and two children) share a chr2q21-p23 insertion on chr7q35-q36, which disrupts the CNTNAP2 gene. This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. The authors speculate that the disruption of CNTNAP2 could lead to a disturbed distribution of potassium (K) channels in neurons, thereby affecting repolarisation of action potentials and causing the TS/OCD/CTD syndrome.

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