A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation

BMC Medical Genetics A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation Ben S Pickard 2 Edward J Hollox 0 M Pat Malloy 1 2 David J Porteous 2 Douglas HR Blackwood 1 John AL Armour 0 Walter J Muir 1 0 Institute of Genetics, Univ. of Nottingham, Queen's Medical Centre , Nottingham, NG7 2UH , UK 1 Psychiatry, Univ. of Edinburgh, Royal Edinburgh Hospital , Morningside Park, Edinburgh, EH10 5HF , UK 2 Medical Genetics, Molecular Medicine Centre, Univ. of Edinburgh, Western General Hospital , Crewe Road, Edinburgh, EH4 2XU , UK Background: Cryptic structural abnormalities within the subtelomeric regions of chromosomes have been the focus of much recent research because of their discovery in a percentage of people with mental retardation (UK terminology: learning disability). These studies focused on subjects (largely children) with various severities of intellectual impairment with or without additional physical clinical features such as dysmorphisms. However it is well established that prevalence of schizophrenia is around three times greater in those with mild mental retardation. The rates of bipolar disorder and major depressive disorder have also been reported as increased in people with mental retardation. We describe here a screen for telomeric abnormalities in a cohort of 69 patients in which mental retardation co-exists with severe psychiatric illness. Methods: We have applied two techniques, subtelomeric fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) to detect abnormalities in the patient group. Results: A subtelomeric deletion was discovered involving loss of 4q in a patient with co-morbid schizoaffective disorder and mental retardation. Conclusion: The precise region of loss has been defined allowing us to identify genes that may contribute to the clinical phenotype through hemizygosity. Interestingly, the region of 4q loss exactly matches that linked to bipolar affective disorder in a large multiply affected Australian kindred. - Background The isolation of unique DNA probes from the sub-telomeric regions of all chromosomes has opened up a field of cytogenetics research that was previously inaccessible to conventional karyotyping protocols [1]. Since then a number of studies have shown that cryptic structural abnormalities (deletions, duplications etc.) in the subtelomeric regions are relatively commonly found in groups of individuals with idiopathic mental retardation (UK; learning disability; LD). The biological attributes of these chromosomal regions may explain this interesting link. The frequency of meiotic recombination is at its highest at the ends of chromosomes (recently confirmed in the Icelandic microsatellite map of the human genome [2]). Therefore errors in this process should randomly result in a greater frequency of unbalanced chromosome rearrangement products at telomeres. There also appears to be a greater density of genes at the ends of some chromosomes, especially those with non-staining R-bands. Thus, any telomeric copy number change is likely to affect several genes; potentially resulting in clinical features typical of a contiguous gene syndrome dysmorphisms, developmental delay and mental retardation. A number of reports have now shown that 0.5%23% of idiopathic mental retardation cases are associated with cryptic translocations in the vicinity of chromosome telomere (see [317] and [18] for a recent review). FISH, using a commercially available set of subtelomeric probes is the most commonly used screening technique [19,20]. Variations on the theme of FISH (e.g. SKY and CGH) have also been employed. More recently, methods that rely on the detection of copy number changes at subtelomeric loci have been described. MAPH [21-24] is one such technique in which probes are representatively amplified by the polymerase chain reaction following hybridisation to a patient's genomic DNA sample to generate a quantitative profile of subtelomeric sequence copy number. Psychiatric disorders such as schizophrenia (SCZ) and bipolar affective disorder (BPAD) are relatively common in the general population and there is much evidence for a genetic component to susceptibility (for a review see [25]). However, it is clear from the lack of consistent findings from linkage mapping and association studies that they are likely to be complex and aetiologically heterogeneous disorders. For example, several genes might act simultaneously (oligogenic action) or interact (epistasis) to produce the clinical phenotype in any individual, and those genes might be different in different individuals (locus heterogeneity). An alternative to cohort based linkage and association approaches uses cytogenetic abnormalities as direct pointers to candidate gene loci and this has been successfully applied to patients with psychiatric disorders resulting in the identification of a number of candidate susceptibility genes including DISC1/DISC2 [26], DIBD1 [27] and GRIA3 [28]. The chromosome abnormalities that disrupted these genes were reciprocal translocations visible by standard cytogenetic methods. The risk of schizophrenia and affective disorders in patients with idiopathic mild mental retardation is significantly raised and it is well established that schizophrenia is three times more common in this group than the general population and that there is a strong familial element [29]. Both bipolar illness and major depressive disorder have also been described as of increased prevalence in the population with mild mental retardation. The study also revealed a previously undetected complex re-arrangement between chromosomes 2 and 11, and a case of trisomy X, but did not address subtelomeric changes. It strongly suggested however that the co-association between mental retardation and schizophrenia is highly familial with greater rates of both schizophrenia and co-morbid schizophrenia/mental retardation occurring in the families of co-morbid probands compared to families of probands with schizophrenia alone or with mental retardation alone. Limbic system (amygdalo-hippocampal) neuropathology is especially pronounced in this group [30]. We have formed the hypothesis that patients who are co-morbid for severe psychiatric illness and mental retardation may be homogenous in their pathophysiology and that, in addition to large-scale structural chromosomal abnormalities, they may harbour as yet undetected cryptic telomeric changes. To test this we have screened a series of 69 patients co-morbid for mental retardation and psychiatric illness using fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH). Methods Patient Cohort Local research ethics permission was obtained for this study. The patients were initially ascertained through computerised psychiatric clinical case-registers that allowed us to identify adults with d (...truncated)