DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.

Transition metal- and solvent-free anti-Markovnikov selective protoboration of alkenes with bis(pinacolato)diboron.

An efficient anti-Markovnikov selective transition metal- and solvent-free Lewis base-mediated protoboration of aromatic and aliphatic alkenes with bis(pinacolato)diboron (B2pin2) as the boron reagent is reported. This protocol is practical and demonstrates broad substrate scope and good functional-group tolerance on alkenes to give synthetically useful alkyl boronate esters in excellent yields under mild reaction conditions. The gram-scale reaction further highlighted the usefulness of this method.

Dissecting the heterogeneity of "in the wild" stress from multimodal sensor data.

Stress is associated with numerous chronic health conditions, both mental and physical. However, the heterogeneity of these associations at the individual level is poorly understood. While data generated from individuals in their day-to-day lives "in the wild" may best represent the heterogeneity of stress, gathering these data and separating signals from noise is challenging. In this work, we report findings from a major data collection effort using Digital Health Technologies (DHTs) and frontline healthcare workers. We provide insights into stress "in the wild", by using robust methods for its identification from multimodal data and quantifying its heterogeneity. Here we analyze data from the Stress and Recovery in Frontline COVID-19 Workers study following 365 frontline healthcare workers for 4-6 months using wearable devices and smartphone app-based measures. Causal discovery is used to learn how the causal structure governing an individual's self-reported symptoms and physiological features from DHTs differs between non-stress and potential stress states. Our methods uncover robust representations of potential stress states across a population of frontline healthcare workers. These representations reveal high levels of inter- and intra-individual heterogeneity in stress. We leverage multiple stress definitions that span different modalities (from subjective to physiological) to obtain a comprehensive view of stress, as these differing definitions rarely align in time. We show that these different stress definitions can be robustly represented as changes in the underlying causal structure on and off stress for individuals. This study is an important step toward better understanding potential underlying processes generating stress in individuals.

Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.

Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.

A simplified approach of prosthetic management of posttraumatic nasal obstruction using a custom-made unilateral intranasal stent in 14-year-old child.

Infections, trauma, iatrogenic causes, congenital malformations, or complications of systemic diseases can result in perforation of the nasal septum. An intranasal stent is a removable prosthesis that can be inserted into the nasal cavity to support the form of nose. The stenting can be used for recanalization and nasal valve preservation. This case report presents a method for the fabrication of a customized nasal stent in a 14-year-old female patient with posttraumatic unilateral collapsed nasal vestibule.

Double Lip-An Atypical Facial Anomaly: Two Case Reports.

Double lip is a rare abnormality. It affects the lips, more often the upper lips and could be acquired or congenital. It may be associated with Ascher's syndrome or occur in isolation. In this deformity, there is an accessory fold of redundant mucous membrane inside the vermillion border. This cupid's bow-shaped accessory tissue is usually conspicuous during smiling but maybe occasionally visible even at rest. For the patient, this atypical facial deformity most importantly creates an aesthetic problem. Nonetheless, it may also interfere with their speech or function. Surgical excision is the treatment of choice and gives appropriate esthetic and functional results. In this article, we have presented two case reports of congenital maxillary double lip. The etiology, clinical presentation, histopathology and treatment of this infrequent anomaly have been discussed. How to cite this article: Kalra N, Tyagi R, Khatri A, Poswal A, Panwar G, Garg K. Double Lip-An Atypical Facial Anomaly: Two Case Reports. Int J Clin Pediatr Dent. 2018;11(5):451-455.

An Appraisal of the Prevalence and Attributes of Traumatic Dental Injuries in the Permanent Anterior Teeth among 7-14-Year-Old School Children of North East Delhi.

AIMS: The aim of this study was to assess the prevalence, associated risk factors, characteristics, and pattern of traumatic dental injuries (TDIs) in the permanent anterior teeth among school children of North East Delhi area. SETTINGS AND DESIGN: A cross-sectional study was done in 3000 school-going children aged 7-14 years. MATERIALS AND METHODS: A detailed case history and clinical examination were performed on the entire sample population. TDIs were recorded according to Andreasen's epidemiological classification of TDIs including World Health Organization codes. STATISTICAL ANALYSIS USED: For finding the independent association of the significant variables with outcome, multivariable logistic regression analysis was used. RESULTS: A prevalence of 10.7% was observed in the sample being studied. Dental trauma was significantly (P < 0.05) associated with male gender, and high statistical significance (P < 0.001) was noted with age, participation in sports, lip seal, and overjet. Fall of the child while playing by himself/herself was the most common cause; afternoon and schools were the most common time and place of occurrence of TDIs, respectively. Single tooth enamel fractures in the left maxillary central incisors were most commonly seen. Adhesive restorations were the most frequent form of treatment required. CONCLUSIONS: Organizing studies addressing the prevention and treatment needs of TDIs and educational programs aimed toward parents and school teachers are of paramount importance. Furthermore, recognizing the tremendous treatment negligence is extremely critical to adequately analyze indifference of the people toward dental trauma and its consequences.

Prosthetic Rehabilitation of an Insidiously Enlarged Traumatic Palatal Perforation after Orotracheal Intubation in a Young Diabetic Child.

This report describes an unusual case of an insidiously enlarged traumatic palatal perforation after orotracheal intubation in a four-year-old female child with Insulin Dependent Diabetes Mellitus (IDDM). The child was first diagnosed with diabetes at 10 months of age when she was hospitalized for pneumonia. Severe respiratory distress warranted assisted ventilation via orotracheal intubation. Multiple factors namely infection, relative immunodeficiency, poor wound healing, trauma via orotracheal intubation as well as uncontrolled glucose levels, all contributed to the formation and deterioration of the palatal perforation. A palatal obturator was fabricated as an interim treatment until surgical closure could be performed.