Wales Infants' and childreN's Genome Service (WINGS): providing rapid genetic diagnoses for unwell children.

INTRODUCTION: This study reviews the first 3 years of delivery of the first National Health Service (NHS)-commissioned trio rapid whole genome sequencing (rWGS) service for acutely unwell infants and children in Wales. METHODS: Demographic and phenotypic data were prospectively collected as patients and their families were enrolled in the Wales Infants' and childreN's Genome Service (WINGS). These data were reviewed alongside trio rWGS results. RESULTS: From April 2020 to March 2023, 82 families underwent WINGS, with a diagnostic yield of 34.1%. The highest diagnostic yields were noted in skeletal dysplasias, neurological or metabolic phenotypes. Mean time to reporting was 9 days. CONCLUSION: This study demonstrates that trio rWGS is having a positive impact on the care of acutely unwell infants and children in an NHS setting. In particular, the study shows that rWGS can be applied in an NHS setting, achieving a diagnostic yield comparable with the previously published diagnostic yields achieved in research settings, while also helping to improve patient care and management.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

Responses to a combined dynamic stretching and antagonist static stretching warm-up protocol on isokinetic leg extension performance.

Antagonist static-stretching and dynamic-stretching are both effective at improving muscular performance. The purpose of this study was to investigate responses to a dynamic stretching warm-up protocol, a static-stretching warm-up protocol and a combined dynamic-stretching and antagonist static stretching warm-up protocol on isokinetic leg extension performance. Twelve participants completed a baseline (PRE) isokinetic knee-extension test at 60°.s-1 and 300°.s-1, following a 5 min warm-up on a cycle ergometer. Subsequently, participants completed the following warm-up protocols randomly over a three-week period: dynamic-stretching (DS); antagonist muscle static-stretching (AMSS) and dynamic followed by antagonist muscle static-stretching (DS-AMSS). A repeated measures analysis of variance (ANOVA) was conducted to determine where significant differences existed for peak torque, total work, average power, time-to-peak-torque and relative peak torque between warm-up protocols. DS-AMSS facilitated a significantly higher peak torque and total work compared to PRE, DS and AMSS at 60°.s-1 and 300°.s-1 P < 0.05, respectively). DS-AMSS caused significantly greater relative peak torque than PRE for 60°.s-1 and 300°.s-1 (P < 0.05). DS-AMSS resulted in significantly reduced time-to-peak-torque and increased average power at 60°.s-1 compared to PRE, DS and AMSS (P < 0.05). DS-AMSS and AMSS resulted in a significant reduction in time-to-peak-torque and increased average power compared to the PRE and DS (P < 0.05) at 300°.s-1.