Successful classification of clinical pediatric leukemia genetic subtypes via structural variant detection using HiFi long-read sequencing.

Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort.

Brain malformations and seizures by impaired chaperonin function of TRiC.

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures.

A taste of space: Remote animal observations and discrete-choice models provide new insights into foraging and density dynamics for a large subarctic herbivore.

Competition for resources and space can drive forage selection of large herbivores from the bite through the landscape scale. Animal behaviour and foraging patterns are also influenced by abiotic and biotic factors. Fine-scale mechanisms of density-dependent foraging at the bite scale are likely consistent with density-dependent behavioural patterns observed at broader scales, but few studies have directly tested this assertion.

Macrocephaly and developmental delay caused by missense variants in RAB5C.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C.

Hyperinsulinemic Hypoglycemia and Growth Hormone Deficiency Secondary to 20p11 Deletion.

Hypoglycemia is concerning for neurological complications in infants and children. Determining the cause of hypoglycemia is essential in providing appropriate treatment. Hyperinsulinism and growth hormone deficiency are known causes of hypoglycemia but are not commonly found together.

Getting off the ladder: Disentangling water quality indices to enhance the valuation of divergent ecosystem services.

Many water quality valuation studies and Federal cost-benefit analyses build from pioneering work using a "water quality ladder" or a single water quality index (WQI) to characterize both current conditions and effects of policies. When policies lead to contrasting changes in valued ecosystem services like recreational fishing and swimming, analyses using a single ladder or index might obscure important underlying service trade-offs. We test for this effect using alternative approaches that separate water quality indices and value changes in distinct ecosystem services stemming from policies with small to moderate changes in water quality.

Integrated genetic profiling of archival pediatric high-grade glial tumors and reassessment with 2021 WHO classification of paediatric CNS tumours.

Though rare, pediatric high-grade gliomas (pHGG) are a leading cause of cancer-related mortality in children. We wanted to determine whether our currently available clinical laboratory methods could better define diagnosis for pHGG that had been archived at our institution for the past 20 years (1998 to 2017). We investigated 33 formalin-fixed paraffin-embedded pHGG using ThermoFisher Oncoscan SNP microarray with somatic mutation analysis, Sanger sequencing, and whole genome sequencing.

Clinical Validation of Genome Reference Consortium Human Build 38 in a Laboratory Utilizing Next-Generation Sequencing Technologies.

Background: Laboratories utilizing next-generation sequencing align sequence data to a standardized human reference genome (HRG). Several updated versions, or builds, have been released since the original HRG in 2001, including the Genome Reference Consortium Human Build 38 (GRCh38) in 2013. However, most clinical laboratories still use GRCh37, which was released in 2009.

Increasing fire frequency and severity will increase habitat loss for a boreal forest indicator species.

Climate change will lead to more frequent and more severe fires in some areas of boreal forests, affecting the distribution and availability of late-successional forest communities. These forest communities help to protect globally significant carbon reserves beneath permafrost layers and provide habitat for many animal species, including forest-dwelling caribou. Many caribou populations are declining, yet the mechanisms by which changing fire regimes could affect caribou declines are poorly understood.

Critical summer foraging tradeoffs in a subarctic ungulate.

Summer diets are crucial for large herbivores in the subarctic and are affected by weather, harassment from insects and a variety of environmental changes linked to climate. Yet, understanding foraging behavior and diet of large herbivores is challenging in the subarctic because of their remote ranges. We used GPS video-camera collars to observe behaviors and summer diets of the migratory Fortymile Caribou Herd () across Alaska, USA and the Yukon, Canada.

Factors Affecting Migration to GRCh38 in Laboratories Performing Clinical Next-Generation Sequencing.

The most recent build of the human reference genome, GRCh38, was released in 2013. However, many laboratories performing next-generation sequencing (NGS) continue to align to GRCh37. Our aim was to assess the number of clinical diagnostic laboratories that have migrated to GRCh38 and discern factors impeding migration for those still using GRCh37.

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features.

Clinical and molecular cytogenetic characterization of a novel 10q interstitial deletion: a case report and review of the literature.

Background: There are only ten reported cases of interstitial deletions involving cytogenetic bands 10q21.3q22.2 in the literature.

Neuroblastoma in Adolescents and Children Older than 10 Years: Unusual Clinicopathologic and Biologic Features.

Neuroblastoma (NB) in children older than 10 years is rare. We reviewed our archives for patients with NB aged 10 to 18 years and summarized their clinicopathologic/genetic records. Of 96 patients, 4 patients were identified in this age group.

Delineating the Clinical Spectrum Associated With Xq25q26.2 Duplications: Report of 2 Families and Review of the Literature.

To date, 13 patients with interstitial microduplications involving Xq25q26.2 have been reported. Here, we report 6 additional patients from 2 families with duplications involving Xq25q26.

Identification of two 14q32 deletions involving DICER1 associated with the development of DICER1-related tumors.

DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia. The majority of reported germline DICER1 mutations are truncating sequence-level alterations, suggesting that a loss-of-function type mechanism drives tumor formation in DICER1 syndrome.

FGF receptors control alveolar elastogenesis.

Alveologenesis, the final step of lung development, is characterized by the formation of millions of alveolar septa that constitute the vast gas-exchange surface area. The genetic network driving alveologenesis is poorly understood compared with earlier steps in lung development. FGF signaling through receptors and is crucial for alveologenesis, but the mechanisms through which they mediate this process remain unclear.

E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors.

The mammalian lung is an elaborate branching organ, and it forms following a highly stereotypical morphogenesis program. It is well established that precise control at the transcript level is a key genetic underpinning of lung branching. In comparison, little is known about how regulation at the protein level may play a role.

Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.

We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray.

Syndactyly in a novel Fras1(rdf) mutant results from interruption of signals for interdigital apoptosis.

Background: Fras1 encodes an extracellular matrix protein that is critical for the establishment of the epidermal basement membrane during gestation. In humans, mutations in FRAS1 cause Fraser Syndrome (FS), a pleiotropic condition with many clinical presentations such as limb, eye, kidney, and craniofacial deformations. Many of these defects are mimicked by loss of Fras1 in mice, and are preceded by the formation of epidermal blisters in utero.

FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching.

The mammalian lung forms its elaborate tree-like structure following a largely stereotypical branching sequence. While a number of genes have been identified to play essential roles in lung branching, what coordinates the choice between branch growth and new branch formation has not been elucidated. Here we show that loss of FGF-activated transcription factor genes, Etv4 and Etv5 (collectively Etv), led to prolonged branch tip growth and delayed new branch formation.

Ontogeny of the mouse vocal fold epithelium.

This investigation provides the first systematic determination of the cellular and molecular progression of vocal fold (VF) epithelium development in a murine model. We define five principal developmental events that constitute the progression from VF initiation in the embryonic anterior foregut tube to fully differentiated and functional adult tissue. These developmental events include (1) the initiation of the larynx and vocal folds with apposition of the lateral walls of the primitive laryngopharynx (embryonic (E) day 10.

Genome-scale study of transcription factor expression in the branching mouse lung.

Background: Mammalian lung development consists of a series of precisely choreographed events that drive the progression from simple lung buds to the elaborately branched organ that fulfills the vital function of gas exchange. Strict transcriptional control is essential for lung development. Among the large number of transcription factors encoded in the mouse genome, only a small portion of them are known to be expressed and function in the developing lung.

Changes in forest productivity across Alaska consistent with biome shift.

Global vegetation models predict that boreal forests are particularly sensitive to a biome shift during the 21st century. This shift would manifest itself first at the biome's margins, with evergreen forest expanding into current tundra while being replaced by grasslands or temperate forest at the biome's southern edge. We evaluated changes in forest productivity since 1982 across boreal Alaska by linking satellite estimates of primary productivity and a large tree-ring data set.

An evolutionarily conserved arginine is essential for Tre1 G protein-coupled receptor function during germ cell migration in Drosophila melanogaster.

Background: G protein-coupled receptors (GPCRs) play central roles in mediating cellular responses to environmental signals leading to changes in cell physiology and behaviors, including cell migration. Numerous clinical pathologies including metastasis, an invasive form of cell migration, have been linked to abnormal GPCR signaling. While the structures of some GPCRs have been defined, the in vivo roles of conserved amino acid residues and their relationships to receptor function are not fully understood.