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Delineation of functionally essential protein regions for 242 neurodevelopmental genes
(2022)
Sumaiya Iqbal
;
Tobias Brünger
;
PEREZ PALMA, EDUARDO ESTEBAN
;
Marie Macnee
;
Andreas Brunklaus
<jats:title>Abstract</jats:title> <jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.</jats:p> <jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.</jats:p> <jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.</jats:p>
1 1Scopus© Citations 11
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Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study
(2022)
Minggui Wang
;
Michelle Earley
;
Liang Chen
;
Blake M Hanson
;
Yunsong Yu
Scopus© Citations 226 7
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Genomic Epidemiology of Vancomycin-Resistant Enterococcus faecium (VREfm) in Latin America: Revisiting The Global VRE Population Structure
(2020)
Rafael Rios
;
Jinnethe Reyes
;
Lina P. Carvajal
;
Sandra Rincon
;
Diana Panesso
<jats:title>Abstract</jats:title><jats:p>Little is known about the population structure of vancomycin-resistant <jats:italic>Enterococcus faecium</jats:italic> (VR<jats:italic>Efm</jats:italic>) in Latin America (LATAM). Here, we provide a complete genomic characterization of 55 representative Latin American VR<jats:italic>Efm</jats:italic> recovered from 1998–2015 in 5 countries. The LATAM VR<jats:italic>Efm</jats:italic> population is structured into two main clinical clades without geographical clustering. Using the LATAM genomes, we reconstructed the global population of VR<jats:italic>Efm</jats:italic> by including 285 genomes from 36 countries spanning from 1946 to 2017. In contrast to previous studies, our results show an early branching of animal related isolates and a further split of clinical isolates into two sub-clades within clade A. The overall phylogenomic structure of clade A was highly dependent on recombination (54% of the genome) and the split between clades A and B was estimated to have occurred more than 2,765 years ago. Furthermore, our molecular clock calculations suggest the branching of animal isolates and clinical clades occurred ~502 years ago whereas the split within the clinical clade occurred ~302 years ago (previous studies showed a more recent split between clinical an animal branches around ~74 years ago). By including isolates from Latin America, we present novel insights into the population structure of VR<jats:italic>Efm</jats:italic> and revisit the evolution of these pathogens.</jats:p>
1Scopus© Citations 47 1
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Detection of heterogeneous vancomycin intermediate resistance in MRSA isolates from Latin America
(2020)
Betsy E Castro
;
Maritza Berrio
;
Monica L Vargas
;
Lina P Carvajal
;
Lina V Millan
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Vancomycin is a common first-line option for MRSA infections. The heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) phenotype is associated with therapeutic failure. However, hVISA isolates are usually reported as vancomycin susceptible by routine susceptibility testing procedures.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To detect and characterize the hVISA phenotype in MRSA isolates causing infections in nine Latin American countries.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We evaluated a total of 1189 vancomycin-susceptible MRSA isolates recovered during 2006–08 and 2011–14. After an initial screening of hVISA using glycopeptide-supplemented agar strategies, the detection of hVISA was performed by Etest (GRD) and Macro-method (MET). Isolates deemed to be hVISA were subjected to population analysis profile/AUC (PAP/AUC) and WGS for further characterization. Finally, we interrogated alterations in predicted proteins associated with the development of the VISA phenotype in both hVISA and vancomycin-susceptible S. aureus (VSSA) genomes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 39 MRSA isolates (3.3%) were classified as hVISA (1.4% and 5.6% in MRSA recovered from 2006–08 and 2011–14, respectively). Most of the hVISA strains (95%) belonged to clonal complex (CC) 5. Only 6/39 hVISA isolates were categorized as hVISA by PAP/AUC, with 6 other isolates close (0.87–0.89) to the cut-off (0.9). The majority of the 39 hVISA isolates exhibited the Leu-14→Ile (90%) and VraT Glu-156→Gly (90%) amino acid substitutions in WalK. Additionally, we identified 10 substitutions present only in hVISA isolates, involving WalK, VraS, RpoB and RpoC proteins.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The hVISA phenotype exhibits low frequency in Latin America. Amino acid substitutions in proteins involved in cell envelope homeostasis and RNA synthesis were commonly identified. Our results suggest that Etest-based methods are an important alternative for the detection of hVISA clinical isolates.</jats:p></jats:sec>
3 1Scopus© Citations 14

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