Comprehensive Gene Panel Testing for Hearing Loss in Children: Understanding Factors Influencing Diagnostic Yield.

Objective: To evaluate factors influencing the diagnostic yield of comprehensive gene panel testing (CGPT) for hearing loss (HL) in children and to understand the characteristics of undiagnosed probands.

Study Design: This was a retrospective cohort study of 474 probands with childhood-onset HL who underwent CGPT between 2016 and 2020 at a single center. Main outcomes and measures included the association between clinical variables and diagnostic yield and the genetic and clinical characteristics of undiagnosed probands.

Hospitalizations Associated With Mental Health Conditions Among Adolescents in the US and France During the COVID-19 Pandemic.

Importance: The COVID-19 pandemic has been associated with an increase in mental health diagnoses among adolescents, though the extent of the increase, particularly for severe cases requiring hospitalization, has not been well characterized. Large-scale federated informatics approaches provide the ability to efficiently and securely query health care data sets to assess and monitor hospitalization patterns for mental health conditions among adolescents.

Objective: To estimate changes in the proportion of hospitalizations associated with mental health conditions among adolescents following onset of the COVID-19 pandemic.

International Analysis of Electronic Health Records of Children and Youth Hospitalized With COVID-19 Infection in 6 Countries.

Importance: Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients.

Objective: To describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19.

Design, Setting, And Participants: This retrospective cohort study included pediatric patients hospitalized between February 2 and October 10, 2020.

Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults.

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue.

International Comparisons of Harmonized Laboratory Value Trajectories to Predict Severe COVID-19: Leveraging the 4CE Collaborative Across 342 Hospitals and 6 Countries: A Retrospective Cohort Study.

Objectives: To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions.

Design: Retrospective cohort study.

Setting: The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe.

International electronic health record-derived COVID-19 clinical course profiles: the 4CE consortium.

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.

A Centralized Approach for Practicing Genomic Medicine.

Next-generation sequencing has revolutionized the diagnostic process, making broadscale testing affordable and applicable to almost all specialties; however, there remain several challenges in its widespread implementation. Barriers such as lack of infrastructure or expertise within local health systems and complex result interpretation or counseling make it harder for frontline clinicians to incorporate genomic testing in their existing workflow. The general population is more informed and interested in pursuing genetic testing, and this has been coupled with the increasing accessibility of direct-to-consumer testing.

Correction: The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

Purpose: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care.

Methods: Three of the nation's leading children's hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements.

Rapid and accurate interpretation of clinical exomes using Phenoxome: a computational phenotype-driven approach.

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies. Despite rapid advancements, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization.

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss.

Purpose: Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management, especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES) is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous.

Lack of association of KATNAL1 gene sequence variants and azoospermia in humans.

Purpose: A recent experiment indicated that a loss of function mutation in the murine Katnal1 gene resulted in male factor infertility due to premature exfoliation of spermatids. This study investigated the relevance of this gene to infertility in humans.

Methods: Multiple methods of genetic analysis were employed to investigate whether mutations in human KATNAL1 have a causative role in male infertility.

Uniparental disomy in the human blastocyst is exceedingly rare.

Objective: To establish whether uniparental disomy (UPD) could represent an outcome of embryonic aneuploidy self-correction and its relevance to preimplantation genetic diagnosis, and to validate a method of UPD detection in limited quantities of cells and determine the frequency of UPD in a large sample size of human blastocysts.

Design: Retrospective observational.

Setting: Academic center for reproductive medicine.

High-throughput carrier screening using TaqMan allelic discrimination.

Members of the Ashkenazi Jewish community are at an increased risk for inheritance of numerous genetic diseases such that carrier screening is medically recommended. This paper describes the development and evaluation of 30 TaqMan allelic discrimination qPCR assays for 29 mutations on 2 different high-throughput platforms. Four of these mutations are in the GBA gene and are successfully examined using short amplicons due to the qualitative nature of TaqMan allelic discrimination.

Evaluation of targeted next-generation sequencing-based preimplantation genetic diagnosis of monogenic disease.

Objective: To investigate the applicability of next-generation sequencing (NGS) to preimplantation genetic diagnosis (PGD); to evaluate semiconductor-based NGS for genetic analysis of human embryos.

Design: Blinded.

Setting: Academic center for reproductive medicine.

Motion of transfer RNA from the A/T state into the A-site using docking and simulations.

The ribosome catalyzes peptidyl transfer reactions at the growing nascent polypeptide chain. Here, we present a structural mechanism for selecting cognate over near-cognate A/T transfer RNA (tRNA). In part, the structural basis for the fidelity of translation relies on accommodation to filter cognate from near-cognate tRNAs.

Outcome of the first electron microscopy validation task force meeting.

This Meeting Review describes the proceedings and conclusions from the inaugural meeting of the Electron Microscopy Validation Task Force organized by the Unified Data Resource for 3DEM (http://www.emdatabank.org) and held at Rutgers University in New Brunswick, NJ on September 28 and 29, 2010.

Examinations of tRNA Range of Motion Using Simulations of Cryo-EM Microscopy and X-Ray Data.

We examined tRNA flexibility using a combination of steered and unbiased molecular dynamics simulations. Using Maxwell's demon algorithm, molecular dynamics was used to steer X-ray structure data toward that from an alternative state obtained from cryogenic-electron microscopy density maps. Thus, we were able to fit X-ray structures of tRNA onto cryogenic-electron microscopy density maps for hybrid states of tRNA.

Computational approaches to modeling viral structure and assembly.

The structures of biological macromolecules and macromolecular assemblies can be experimentally determined by X-ray crystallography, nuclear magnetic resonance (NMR), and cryo-electron microscopy (cryo-EM). The refinement of such structures is a difficult task, because of the size of the experimental data sets, and because of the very large number of degrees of freedom. Molecular modeling tools-particularly those based on the principles of molecular mechanics-have long been employed to assist in the refinement of macromolecular structures.

EMDataBank.org: unified data resource for CryoEM.

Cryo-electron microscopy reconstruction methods are uniquely able to reveal structures of many important macromolecules and macromolecular complexes. EMDataBank.org, a joint effort of the Protein Data Bank in Europe (PDBe), the Research Collaboratory for Structural Bioinformatics (RCSB) and the National Center for Macromolecular Imaging (NCMI), is a global 'one-stop shop' resource for deposition and retrieval of cryoEM maps, models and associated metadata.