Copy number variant risk loci for schizophrenia converge on the BDNF pathway.

OBJECTIVES: Schizophrenia genetics is intricate, with common and rare variants' contributions not fully understood. Certain copy number variations (CNVs) elevate risk, pivotal for understanding mental disorder models. Despite CNVs' genome-wide distribution and variable gene and protein effects, we must explore beyond affected genes to interaction partners and molecular pathways. METHODS: In this study, we developed machine-readable interactive pathways to enable analysis of functional effects of genes within CNV loci and identify ten common pathways across CNVs with high schizophrenia risk using the WikiPathways database, schizophrenia risk gene collections from GWAS studies, and a gene-disease association database. RESULTS: For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signalling, cytoskeleton, and inflammation. Common schizophrenia risk genes identified by different studies are found in all CNV pathways, but not enriched. CONCLUSIONS: Our findings suggest that specific pathways - BDNF signalling - are critical contributors to schizophrenia risk conferred by rare CNVs. Our approach highlights the importance of not only investigating deleted or duplicated genes within pathogenic CNV loci, but also study their direct interaction partners, which may explain pleiotropic effects of CNVs on schizophrenia risk and offer a broader field for interventions.

Hearing loss and history of otolaryngological conditions in adults with microdeletion 22q11.2.

Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16-74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full-scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high-frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that  in 22q11.2DS, high-frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high-frequency ranges.

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

Post-traumatic stress in adults with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden.

Ocular findings in 22q11.2 deletion syndrome: A systematic literature review and results of a Dutch multicenter study.

The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in expression and include speech- and language delay, intellectual disability, and neuropsychiatric disorders. We aim to provide an overview of ocular findings in 22q11.2DS in order to optimize recommendations for ophthalmic screening. We combined results from a systematic literature review with results from a multicenter cross-sectional study of patients with 22q11.2DS who were assessed by an ophthalmologist. Our systematic literature search yielded four articles, describing 270 patients. We included 132 patients in our cross-sectional study (median age 8.9 [range 0-56] years). Most reported ocular findings were retinal vascular tortuosity (32%-78%), posterior embryotoxon (22%-50%), eye lid hooding (20%-67%), strabismus (12%-36%), amblyopia (2%-11%), ptosis (4%-6%), and refractive errors, of which hyperopia (6%-48%) and astigmatism (3%-23%) were most common. Visual acuity was (near) normal in most patients (91%-94%). Refractive errors, strabismus, and amblyopia are treatable conditions that are frequently present in patients with 22q11.2DS and should be corrected at an early stage. Therefore, in 22q11.2DS, we recommend ophthalmic and orthoptic screening at the age of 3 years or at diagnosis, and a low-threshold referral in adults.