Purpose Standardized and accurate variant assessment is essential for effective medical care. To that end, Clinical Genome (ClinGen) Resource clinical domain working groups (CDWG) are systematically reviewing disease-associated genes for sufficient evidence to support disease causality and creating disease-specific specifications of ACMG-AMP guidelines for consistent and accurate variant classification. Methods The ClinGen RASopathy CDWG established an expert panel (EP) to curate gene information and generate gene and disease-specific specifications to ACMG-AMP variant classification framework. These specifications were tested by classifying 37 exemplar pathogenic variants plus an additional 66 variants in ClinVar distributed across nine RASopathy genes. Results RASopathy-related specifications were applied to sixteen ACMG-AMP criteria, with five also having adjustable strength with availability of additional evidence. Another five criteria were deemed not applicable. Key adjustments to minor allele frequency thresholds, multiple de novo occurrence events and/or segregation, and strength adjustments impacted 60% of variant classifications. Unpublished case-level data from participating laboratories impacted 45% of classifications supporting the need for data sharing. Conclusions RAS-specific ACMG-AMP specifications optimized the utility of available clinical evidence and Ras/MAPK pathway-specific characteristics to consistently classify RASopathy-associated variants. These specifications highlight how grouping genes by shared features promotes rapid multi-genic variant assessment without sacrificing specificity and accuracy.

Resonant two-photon ionization spectroscopy of jet-cooled tantalum carbide, TaC

BackgroundAxenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition.MethodsGenetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses.Results128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS.ConclusionSince clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Purpose: Limb Girdle Muscular Dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a reliable and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs. Methods: Taking advantage of recently published whole exome and genome sequencing data from the general population, we used a Bayesian method to develop a reliable disease prevalence estimator. Results: This method was applied to nine recessive LGMD subtypes. The estimated disease prevalence calculated by this method were largely comparable to published estimates from epidemiological studies, however highlighted instances of possible under-diagnosis for LGMD2B and 2L. Conclusion: The increasing size of aggregated population variant databases will allow for robust and reproducible prevalence estimates of recessive disease, which is critical for the strategic design and prioritization of clinical trials..

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Experimental profiles of the intermediate species H, OH, CH, CF, CF 2 , and CHF are obtained in a 10 torr premixed flat flame of methane/oxygen in a 1:2 molar ratio, inhibited by a 4% mole fraction of 2-H heptafluoropropane (HFP, CF 3 CHFCF 3 ). These data are compared to calculations using a recently published kinetic mechanism describing the consumption of this fire suppression agent. The profiles in the flame inhibited by HFP are compared to previously published data for flames containing CHF 3 and CH 2 F 2 under the same conditions of stoichiometry and flux of fluorine atoms. The species profiles relative to the flames containing the fluoromethanes are accurately predicted and atmospheric pressure flame speeds are fairly well predicted by the kinetic mechanism. Under equal fluorine loadings, profiles of temperature and of H and OH mole fraction are virtually identical between the flames containing HFP and CHF 3 . The flame inhibited by HFP, however, has approximately twice as much CH* emission as the flame containing CHF 3 . The kinetic model predicts that thermal decomposition, rather than H atom abstraction, is the primary destruction mechanism for HFP under the conditions studied.