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Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families, recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two% of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families, and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialised bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity. The project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. YO is supported by the Turkish Academy of Sciences’ Young Investigator award, TÜBA-GEBİP (2017). PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. Data was analysed using the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement nº 305444) and funding from EJP-RD and INB/ELIXIR-ES. The study was further supported by the Horizon 2020 research and innovation program via grant 779257 “Solve-RD” (RH, SB, AT and HL). RH, PFC and YO were supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1

In this study, the concentration of sub-micron particulate matter (PM) and its associated metals concentration have been discussed. Monitoring of sub-micron particulate matter has been made by using Leland legacy sample pump with five-stage Sioutas Cascade Impactor. Total, 150 samples from urban and sub urban areas of western part of India were analysed using ICP-OES. For PM1.0–2.5, PM0.50–1.0 and PM0.25–0.50 the average mass concentration ranged from 28.33 to 38.86 µg m−3, 30.46 to 39.44 µg m−3, 25.43 to 46.30 µg m−3 for indoor environment, while outdoor environment concentrations ranged from 23.15 to 54.01 µg m−3, 22.38 to 36.20 µg m−3, 22.32 to 44.30 µg m−3, respectively. On the other hand, in sub urban area, the average mass concentrations ranged from 23.15 to 69.44 µg m−3, 27.72 to 51.73 µg m−3, 17.72 to 54.01 µg m−3 for indoor environment, while for outdoor environment, the average mass concentrations ranged from 30.86 to 77.16 µg m−3, 23.15 to 54.01 µg m−3, 24.25 to 46.30 µg m−3 for PM1.0–2.5, PM0.50–1.0 and PM0.25–0.50, respectively. Among all eight toxic metals, Al and Fe were found to be abundant. Human health risk factor also being calculated which showed that these metals were threat to human life. The sources of the sub-micron particulate matter associated metals in outdoor air were found to be the emissions from industries, vehicular activities, and dust from construction sites and in indoor it was mostly from cooking, cleaning and other human activities.

PM(2.5) particulate matter (PM) and their associated polycyclic aromatic hydrocarbons (PAHs) were studied at Urban and Sub-urban sites in the western coast of India. The concentration of PM(2.5) ranged from 66.29 μg m(−3) to 182.15 μg m(−3), being the highest at Sub-urban site than the urban site. There were total six carcinogenic PAHs found to be dominated in particulate samples at these locations. The general trends observed for individual carcinogenic PAHs concentration at urban location was, benzo(a)pyrene (BaP)

Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1β in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1β in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.