Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Prognostic value of serum angiotensin-converting enzyme activity for outcome of community-acquired pneumonia.

BACKGROUND: In a previous study, a relation between decreased serum angiotensin-converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community-acquired pneumonia. METHODS: This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004-2006; n=157 and 2007-2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups. RESULTS: A total of 265 patients were enrolled in this study. Mean age was 60±19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (≥20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57-9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality. CONCLUSIONS: This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia.

The Fcgamma receptor IIA-R/R131 genotype is associated with severe sepsis in community-acquired pneumonia.

Community-acquired pneumonia (CAP) can be caused by a variety of microorganisms but is most frequently associated with Streptococcus pneumoniae and gram-negative bacteria like Haemophilus influenzae. Encapsulated bacteria are able to escape phagocytosis, unless they are bound by immunoglobulin G2 subclass antibodies. These antibodies interact with Fcgamma receptor IIa (Fcgamma-RIIa), thereby facilitating opsonophagocytosis of the encapsulated bacteria. We studied the relationship between the Fcgamma-RIIa-R/H131 polymorphism and the clinical course of CAP and pathogen-specific susceptibility. Regarding methodology, the Fcgamma-RIIa genotype R/H131 was determined in 200 patients with CAP and in 313 healthy controls and was correlated with the clinical course, laboratory parameters, and causative microorganism. The Fcgamma-RIIa-R/R131 genotype was found more frequently in patients with severe sepsis (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.30 to 5.00; P < 0.01). The majority of patients in this group suffered from invasive pneumococcal disease. The duration of hospital stay was longer for patients with the Fcgamma-RIIa-R/R131 genotype. Fcgamma-RIIa genotypes were not associated with an increased risk of CAP in general; however, the Fcgamma-RIIa-R/R131 genotype was found more frequently in patients with CAP caused by H. influenzae than in controls (OR, 3.03; CI, 1.04 to 9.09; P < 0.05). In conclusion, the Fcgamma-RIIa-R/R131 genotype is associated with severity of CAP and is more frequent in CAP caused by H. influenzae.