Phd in HUMAN BIOLOGY AND MEDICAL GENETICS

Thesis title: Neuropsychiatric features and genetic aspects in 22q11.2 deletion syndrome

Introduction. 22q11.2 Deletion Syndrome (22q11.2DS; MIM #192430, MIM #188400) is the most common recurrent microdeletion in humans. The phenotypic spectrum of this syndrome encompasses a heterogeneous range of manifestations. The psychiatric and neurocognitive features have received an increasing attention over the last years and 22q11.2DS is considered as the genetic model of schizophrenia. However, the neurological manifestations are far from being fully clarified. Based on these considerations, in our study we selected an adult population of patients with an established molecular diagnosis of 22q11.2DS and we described the neuropsychiatric features focusing on the neurological manifestations and investigating their possible correlation with general clinical features and genomic size deletion. Methods. All subjects were evaluated by a multidisciplinary team. The neuropsychiatric features were investigated by means of clinical, neurophysiological evaluation (video-EEG) and neuroimaging (Brain MRI). All clinical data regarding patient's neuropsychiatric history and general medical comorbidities were collected and integrated with instrumental data. As regards the genomics, for each patient with an a-CGH test, we evaluated the deletion length and gene content. For selected cases also CNVs outside the 22q deleted region were considered Results. We enrolled 85 adult patients with a confirmed genetic diagnosis of 22q11.2DS. The molecular diagnosis was made by using FISH approach in 46 cases and a-CGH in 39 patients. Twenty-seven patients had a LCR22 A-D deletion. Further potential pathogenic CNVs were analyzed in 26/39 patients and only in six cases additional CNVs were detected. About 88% of patients has a de novo deletion. The 22q11.2 deletion results from variable-sized deleted regions, ranging from small deletions to a typically deleted region of ~3 Mb. Twenty-four patients were left-handed. Twenty-eight subjects had a low IQ, and 30 of 85 subjects had psychotic disorders. Twenty-two patients reported at least one seizure in their lifetime, and twelve were diagnosed with epilepsy. Video-EEG recordings revealed generalized epileptiform abnormalities in 34 of 85 cases. Besides, only one patient with epilepsy had a cardiac malformation. Lastly, 34 subjects presented with parkinsonism 19 of whom were taking neuroleptics. None of the 15 patients with parkinsonism, not related to neuroleptic therapy, was diagnosed with epilepsy. 52 patients performed a brain MRI that disclosed, in most of cases, a white matter gliosis not associated with specific pathologic entity. Conclusions. 22q11.2DS is characterized by left-handedness and neuropsychiatric features such as cognitive impairment, schizophrenia, epilepsy and parkinsonism. Generalized genetic epilepsy, mostly the juvenile myoclonic epilepsy phenotype, is the predominant epilepsy type. The significant association between 22q11.2DS and parkinsonian features confirms patients’ genetic susceptibility to parkinsonism. Despite the lack of conclusive evidence, our study suggests a possible relationship between the analyzed clinical variables: (1) an inverse correlation between low IQ/psychosis/epilepsy and major cardiac diseases; (2) a direct association between psychosis and both mental delay and epilepsy; and (3) an inverse correlation between parkinsonism and epilepsy. Referring the correlation to cytogenetic analysis, neuropsychiatric aspects appear to be part of the phenotype associated with the “typical” (LCR22-A to LCR22-D) deletion or “minimal critical” (LCR22-A to LCR22-B) deletion. This suggests that the relevant genes for neuropsychiatric manifestations could be located within the “minimal critical” region. Among the patients that performed a-CGH, six had a rare CNVs outside 22q11.2 deletion region. In all cases, patients carried the “typical” 22q11.2 deletion.