Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families, and homozygous loss of function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

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BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism may play a role in the pathogenesis of coronavirus-19 disease (COVID-19). OBJECTIVES: Investigate the relationship between ACE I/D polymorphism and the clinical severity of COVID-19. DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. PATIENTS AND METHODS: The study included COVID-19 patients with asymptomatic, mild, and severe disease with clinical data and whole blood samples collected from 1 April 2020 to 1 July 2020. ACE I/D genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. MAIN OUTCOME MEASURE: ACE DD, DI and II genotypes frequencies. SAMPLE SIZE: 90 cases, 30 in each disease severity group. RESULTS: Age and the frequency of general comorbidity increased significantly from the asymptomatic disease group to the severe disease group. Advanced age, diabetes mellitus and presence of ischemic heart disease were independent risk factors for severe COVID-19 [OR and 95 % CI: 1.052 (1.021-1.083), 5.204 (1.006-26.892) and 5.922 (1.109-31.633), respectively]. The ACE II genotype was the dominant genotype (50%) in asymptomatic patients, while the DD genotype was the dominant genotype (63.3 %) in severe disease. The ACE II geno-type was protective against severe COVID-19 [OR and 95% CI: .323 (.112-.929)]. All nine patients (8.9%) who died had severe disease. CONCLUSIONS: The clinical severity of COVID-19 infection may be associated with the ACE I/D polymorphism. LIMITATIONS: Small sample size and single center. CONFLICT OF INTEREST: None.

IntroductionOur aim is to evaluate the influence of clinical and histopathological parameters, including age, gender, tumor stage, grade, tumor differentiation, necrosis, lymphovascular/perineural invasion (LVI/PNI) and concomitant carcinoma in situ (CIS), on outcomes of patients with urothelial carcinoma of the bladder (UCB).Material and methodsA total of 84 patients who underwent radical cystectomy (RC) (n = 11) and radical cystoprostatectomy (n = 73) for muscle-invasive bladder cancer at our hospital between 2007-2013, were included in the study.ResultsThe mean age of patients at diagnosis was 66.1, of whom 75 were males and 9 were females. Of the 84 patients, 38 were ≤65 years and 46 were >65 years. Mean tumor diameter was 3.66 cm. There were 38 cases which showed divergent differentiations. Concomitant CIS was observed in 30 tumors, 41 cases showed tumor necrosis, 44 PNI and 61 LVI.The rate of overall survival (OS) in patients aged ≤65 years was statistically significantly higher than in those aged >65 years. A negative statistical relationship was found between OS with lymph node metastasis (LNM) and tumor differentiation. On the other hand, necrosis did not remain significant on multivariate analysis.No statistically significant relationship was found between smoking, tumor stage, PNI, LVI and concomitant CIS and OS.ConclusionsIn this study, advanced age, LNM, tumor differentiation were found to be independent prognostic risk factors associated with OS after RC. These additional factors, which may explain the different clinical course in patients with similar tumor stage and lymph node status, should be taken into consideration in treatment planning.

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