In the upcoming seminar, five speakers will talk about the rare disease "22q11.2 deletion syndrome" from a genetics, bioinformatics, and clinical perspective. 

Zoom link: https://maastrichtuniversity.zoom.us/j/96925871010 

Speakers

Dr. Friederike Ehrhart

Assistant professor
Department of Bioinformatics - BiGCaT, NUTRIM and Department of Psychiatry and Neuropsychology, MHeNs

Title: Molecular pathway of the 22q11.2 region
Abstract: 22q11.2 deletion syndrome is a rare genetic disorder caused by a deletion of an about 300 MB sized region in chromosome 22. In this region, there are currently 102 genes described of which 51 are protein-coding. The deletion of these genes in one chromosome has a significant effect on the patient's phenotype which is typically characterized by cardiac and palatal abnormalities, immune deficiencies, intellectual and learning disabilities, and increased risk for developing schizophrenia. However, the phenotype varies greatly between patients. The first step to investigate the complex genotype-phenotype relationships was to create a machine-readable pathway that collects available knowledge on the deleted genes' original function and allows further automated analysis of data. For 36 of these protein-coding genes in the region it was yet possible to find interaction partners and downstream pathways, for 15 this is still unknown. The pathway is available at the open, community-created, expert-curated database WikiPathways: www.wikipathways.org/instance/WP4657. The most striking observation of this pathway was that observed phenotypes can be caused or influenced not by one but multiple genes in this region, although TBX1 was thought to be mainly responsible for heart defects. 

Woosub Shin

PhD candidate
Department of Bioinformatics - BiGCaT, NUTRIM

Title: Applying pathway interaction method to hypothesize molecular signature of neuropsychiatric diseases caused by 22q11.2 deletion syndrome.
Abstract: In this study, we explore the Pathway Interaction Method, originally proposed by Kelder et al. (2011), to examine biological processes significantly affected by the 22q11.2 Deletion Syndrome. Specifically, our focus is to identify the molecular signature that is characteristic among patients experiencing neuropsychiatric disorders. Based on the results of our analysis, we argue that, with proper adjustments, the pathway interaction method can give a coherent biological interpretation, complementing conventional pathway methods such as over-representation analysis.

Chaira Serrarens

PhD candidate
Department of Psychiatry and Neuropsychology, MHeNs

Title: The role of glutamate and GABA in cognition in subjects with chromosome 22q11.2 copy number variants.
Abstract: 22q11.2 copy number variants (22q11.2 CNVs) are associated with an increased risk of developing a variety of psychiatric disorders, including psychotic disorders, and cognitive dysfunction. Glutamatergic pathways have been linked with psychosis and cognition and are hypothesized to be disrupted in 22q11.2 CNV patients, possibly ‘shifting’ the excitatory (glutamate) /inhibitory (GABA) balance. Although a balance between both glutamate and GABA is necessary for optimal brain functioning, both systems are often studied in isolation, and little is known about GABA in 22q11.2 CNVs. Using magnetic resonance spectroscopy (MRS) we will investigate the role of glutamate and GABA in cognition in 22q11.2 CNVs.

Dr. Ana Silva

Department of Psychiatry and Neuropsychology, MHeNs

Title: New targets in psychiatric research: identifying convergent molecular pathways leading to shared effects on brain structure across pathogenic copy number variants.
Abstract: Recent findings have revealed convergent effects of multiple CNVs on different chromosomes, on core sensory, cognitive, and motor domains. Furthermore, recent evidence showed that the penetrance of a CNV for schizophrenia and developmental delay – reflecting the probability of manifesting the given phenotype – was associated with changes in medial white matter structures. These results suggest that different pathogenic CNVs lead to convergent phenotypes by causing similar disruptions in the brain and that these disruptions may be associated with the penetrance of the CNV. I will present my VENI proposal, which seeks to develop a multidisciplinary approach to combine neuroimaging data, biological pathway knowledge from prior knowledge databases, and animal models, in order to find specific cellular mechanisms that underlie convergent cross-CNV effects on brain structure. In the first part of the project, I will use neuroimaging data from international collaborations with ENIGMA-CNV and ENIGMA-22q working groups. This unique neuroimaging dataset comprised hundreds of carriers of variable penetrant CNVs (n=~25), with more than 300 carriers of the 22q11.2 deletion. Here, I will look for associations between measures of volume, cortical thickness, and surface area (extracted from T1-weighted MRI data) and penetrance scores for schizophrenia and development delay, previously calculated for each CNV.

Emma von Scheibler

PhD candidate
Department of Psychiatry and Neuropsychology, MHeNs

Title: Ocular findings in 142 individuals with 22q11.2 deletion syndrome
Abstract: 22q11.2 deletion syndrome (22q11.2DS) is a multi-system disorder caused by heterozygous microdeletions on chromosome 22q11.2, with an incidence of 1:3000 live births. Characteristics include congenital birth defects, intellectual disability, and neuropsychiatric disorders. Previous studies on ocular findings in children reported an increased prevalence of refractive errors and strabismus. A retrospective chart review of individuals with 22q11.2DS who underwent an ophthalmic examination in one of three Dutch hospitals. Visual acuity, refraction, orthoptic, fundoscopy, and slit-lamp results were extracted. One hundred and forty-two individuals (44% male, median age 8.5 (0.0-56.8) years) were included. Retinal tortuosity was reported in 32%, posterior embryotoxon in 21%, strabismus in 13%, optic disk abnormalities in 15%, and amblyopia in 11%. Three percent had low vision (≥0.5 logMAR). The majority of individuals had mild (33%), moderate (24%), or severe (18%) farsightedness. Nearsightedness was seen in 13%. High astigmatism was seen in 27% of individuals. Weak positive correlations were found between age and astigmatism (p<0.05, R 0.2-0.3) and a shift from farsightedness towards nearsightedness with age (p<0.05, R0.24-0.26). Conclusion Clinicians should be aware of strabismus and amblyopia in 22q11.2DS at a young age and refractive errors at all ages.