Classification of feline hypertrophic cardiomyopathy-associated gene variants according to the American College of Medical Genetics and Genomics guidelines

IntroductionThe correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification.MethodsGenetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated. In silico evaluation followed with joint evidence and data from other publications assisting in the classification of each variant.ResultsTwo variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance.DiscussionRoutine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial

Hybrid PET- and MR-driven attenuation correction for enhanced ¹⁸F-NaF and ¹⁸F-FDG quantification in cardiovascular PET/MR imaging

Background: The standard MR Dixon-based attenuation correction (AC) method in positron emission tomography/magnetic resonance (PET/MR) imaging segments only the air, lung, fat and soft-tissues (4-class), thus neglecting the highly attenuating bone tissues and affecting quantification in bones and adjacent vessels. We sought to address this limitation by utilizing the distinctively high bone uptake rate constant Ki expected from ¹⁸F-Sodium Fluoride (¹⁸F-NaF) to segment bones from PET data and support 5-class hybrid PET/MR-driven AC for ¹⁸F-NaF and ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) PET/MR cardiovascular imaging. Methods: We introduce 5-class Ki/MR-AC for (i) ¹⁸F-NaF studies where the bones are segmented from Patlak Ki images and added as the 5th tissue class to the MR Dixon 4-class AC map. Furthermore, we propose two alternative dual-tracer protocols to permit 5-class Ki/MR-AC for (ii) ¹⁸F-FDG-only data, with a streamlined simultaneous administration of ¹⁸F-FDG and ¹⁸F-NaF at 4:1 ratio (R4:1), or (iii) for ¹⁸F-FDG-only or both ¹⁸F-FDG and ¹⁸F-NaF dual-tracer data, by administering ¹⁸F-NaF 90 minutes after an equal ¹⁸F-FDG dosage (R1:1). The Ki-driven bone segmentation was validated against computed tomography (CT)-based segmentation in rabbits, followed by PET/MR validation on 108 vertebral bone and carotid wall regions in 16 human volunteers with and without prior indication of carotid atherosclerosis disease (CAD). Results: In rabbits, we observed similar (< 1.2% mean difference) vertebral bone ¹⁸F-NaF SUVmean scores when applying 5-class AC with Ki-segmented bone (5-class Ki/CT-AC) vs CT-segmented bone (5-class CT-AC) tissue. Considering the PET data corrected with continuous CT-AC maps as gold-standard, the percentage SUVmean bias was reduced by 17.6% (¹⁸F-NaF) and 15.4% (R4:1) with 5-class Ki/CT-AC vs 4-class CT-AC. In humans without prior CAD indication, we reported 17.7% and 20% higher ¹⁸F-NaF target-to-background ratio (TBR) at carotid bifurcations wall and vertebral bones, respectively, with 5- vs 4-class AC. In the R4:1 human cohort, the mean ¹⁸F-FDG:¹⁸F-NaF TBR increased by 12.2% at carotid bifurcations wall and 19.9% at vertebral bones. For the R1:1 cohort of subjects without CAD indication, mean TBR increased by 15.3% (¹⁸F-FDG) and 15.5% (¹⁸F-NaF) at carotid bifurcations and 21.6% (¹⁸F-FDG) and 22.5% (¹⁸F-NaF) at vertebral bones. Similar TBR enhancements were observed when applying the proposed AC method to human subjects with prior CAD indication. Conclusions: Ki-driven bone segmentation and 5-class hybrid PET/MR-driven AC is feasible and can significantly enhance ¹⁸F-NaF and ¹⁸F-FDG contrast and quantification in bone tissues and carotid walls

VariantscanR: an R-package as a clinical tool for variant filtering of known phenotype-associated variants in domestic animals

Abstract Background Since the introduction of next-generation sequencing (NGS) techniques, whole-exome sequencing (WES) and whole-genome sequencing (WGS) have not only revolutionized research, but also diagnostics. The gradual switch from single gene testing to WES and WGS required a different set of skills, given the amount and type of data generated, while the demand for standardization remained. However, most of the tools currently available are solely applicable for human analysis because they require access to specific databases and/or simply do not support other species. Additionally, a complicating factor in clinical genetics in animals is that genetic diversity is often dangerously low due to the breeding history. Combined, there is a clear need for an easy-to-use, flexible tool that allows standardized data processing and preferably, monitoring of genetic diversity as well. To fill these gaps, we developed the R-package variantscanR that allows an easy and straightforward identification and prioritization of known phenotype-associated variants identified in dogs and other domestic animals. Results The R-package variantscanR enables the filtering of variant call format (VCF) files for the presence of known phenotype-associated variants and allows for the estimation of genetic diversity using multi-sample VCF files. Next to this, additional functions are available for the quality control and processing of user-defined input files to make the workflow as easy and straightforward as possible. This user-friendly approach enables the standardisation of complex data analysis in clinical settings. Conclusion We developed an R-package for the identification of known phenotype-associated variants and calculation of genetic diversity

ESPEN practical guideline: Home parenteral nutrition

This guideline will inform physicians, nurses, dieticians, pharmacists, caregivers and other home parenteral nutrition (HPN) providers, as well as healthcare administrators and policy makers, about appropriate and safe HPN provision. This guideline will also inform patients requiring HPN. The guideline is based on previous published guidelines and provides an update of current evidence and expert opinion; it consists of 71 recommendations that address the indications for HPN, central venous access device (CVAD) and infusion pump, infusion catheter and CVAD site care, nutritional admixtures, program monitoring and management. Meta-analyses, systematic reviews and single clinical trials based on clinical questions were searched according to the PICO format. The evidence was evaluated and used to develop clinical recommendations implementing Scottish Intercollegiate Guidelines Network methodology. The guideline was commissioned and financially supported by ESPEN and members of the guideline group were selected by ESPEN