The research presented in this thesis is centered around one question: What can we learn from the study of psychiatric phenotypes related to structural genomic abnormalities? In this thesis this subject is examined, with most studies focused on the clinical and genetic aspects of the 22q11.2 deletion syndrome. In chapter 1 a review of all published case-reports on individuals with autism and a concurrent structural genetic abnormality is presented. In chapter 2 findings are presented of a study on the psychiatric phenotype of 22q11DS. In a sample of 60 Dutch children aged with 22q11DS, 50% were diagnosed with an autism spectrum disorder, 12% were diagnosed with a psychotic disorder and 8% were found to have a mood disorder. In chapter 3 the test characteristics of a novel method for the detection of copy number changes, Multiplex Ligation-dependent Probe Amplification (MLPA), are reported. The results demonstrate that MLPA reliably identifies typical and atypical 22q11.2 copy number changes. The sensitivity and specificity of MLPA were 0.99 and 0.97, respectively. However, there were still rare structural genomic abnormalities that would not have been detected by the available MLPA kit,therefore, an effort was made to develop a new MLPA set with an increased density of probes across the 22q11.2 region. The results of this effort are reported in chapter 4. In chapter 5 the MLPA method was used to screen a sample of 311 Dutch patients with schizophrenia for the presence of 22q11.2 deletions. The sample included 146 patients with prominent negative symptoms (deficit schizophrenia). The hypothesis of an increased prevalence of 22q11.2 deletions in this subgroup was not confirmed; indeed none of the 311 patients was found to have a deletion at 22q11.2. In chapter 6 a significant interaction between high plasma proline and the COMTmet allele on a neurophysiologic test paradigm; Smooth Pursuit of the Eye Movement is demonstrated in a sample of children with 22q11DS, In chapter 7 a significant interaction is presented between a previously reported schizophrenia-risk allele of the gene PIK4CA and schizophrenia. The PIK4CA risk allele was significantly more present in a group of adult 22q11DS patients with schizophrenia in comparison to adult 22q11DS patients without schizophrenia. In chapter 8 the clinical and molecular genetic findings are reported concerning a normally intelligent proband with autism who was found to carry a maternally inherited large deletion (~10Mb) of chromosome 13q. Because his mother was not affected with autism, it was hypothesized that the proband could have a functional mutation in a remaining allele of one of the genes located in the deleted region. The results from the sequencing studies confirmed this “double hit” hypothesis; the proband carried a paternally inherited non-synonymous point mutation in DIAPH3, one of the genes in the region affected by the maternally inherited deletion. In conclusion, results of the presented research favor the view that studying psychiatric phenotypes associated with structural genomic abnormalities may generate valuable information about the genetic, and thus the biological factors that lead to psychiatric disorders, such as autism and schizophrenia
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