Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ∼50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene, SMARCB1-a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

As atherosclerosis begins in childhood, early diagnosis and treatment of familial hypercholesterolemia (FH) is considered necessary. The basic diagnosis of pediatric FH (under 15 years of age) is based on hyper-low-density lipoprotein (LDL) cholesterolemia and a family history of FH; however, in this guideline, to reduce overlooked cases, \"probable FH\" was established. Once diagnosed with FH or probable FH, efforts should be made to promptly provide lifestyle guidance, including diet. It is also important to conduct an intrafamilial survey, to identify family members with the same condition. If the level of LDL-C remains above 180 mg/dL, drug therapy should be considered at the age of 10. The first-line drug should be statin. Evaluation of atherosclerosis should be started using non-invasive techniques, such as ultrasound. The management target level is an LDL-C level of less than 140 mg/dL. If a homozygous FH is suspected, consult a specialist and determine the response to pharmacotherapy with evaluating atherosclerosis. If the response is inadequate, initiate lipoprotein apheresis as soon as possible.

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Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.
An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power.
Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm2) significantly influences PFS (P = .0098) and marginally the OS (P = .07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data.
The mitotic index (cut-off 2 per 10 40× HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.

The overall prevalence of uniparental disomy (UPD) across all chromosomes was estimated to be around one birth in 2000. To date, more than 4170 UPD cases have been registered. UPD for chromosomes 6, 7, 11, 14, 15, and 20 can result in clinically recognizable imprinting disorders due to abnormal levels of imprinted gene expression. For other chromosomes, the clinical consequences associated with UPD are not apparent, unless when a recessive genetic disorder is unmasked by UPD or regions of homozygosity (ROH). A clinical practice guideline will assist in strengthening the precise analysis and interpretation of the clinical significance of ROH/UPD. This guideline summarizes the conception, mechanism and clinical consequences of ROH/UPD, as well as the principles for data analysis, with an aim to standardize the clinical application and data interpretation.

The overall prevalence of uniparental disomy (UPD) across all chromosomes was estimated to be around one birth in 2000. To date, more than 4170 UPD cases have been registered. UPD for chromosomes 6, 7, 11, 14, 15, and 20 can result in clinically recognizable imprinting disorders due to abnormal levels of imprinted gene expression. For other chromosomes, the clinical consequences associated with UPD are not apparent, unless when a recessive genetic disorder is unmasked by UPD or regions of homozygosity (ROH). A clinical practice guideline will assist in strengthening the precise analysis and interpretation of the clinical significance of ROH/UPD. This guideline summarizes the conception, mechanism and clinical consequences of ROH/UPD, as well as the principles for data analysis, with an aim to standardize the clinical application and data interpretation.

BACKGROUND: Genomic regions with a high frequency of runs of homozygosity (ROH) are related to important traits in farm animals. We carried out a comprehensive analysis of ROH and evaluated their association with production traits using the BovineHD (770 K) SNP array in Chinese Simmental beef cattle.
RESULTS: We detected a total of 116,953 homozygous segments with 2.47Gb across the genome in the studied population. The average number of ROH per individual was 99.03 and the average length was 117.29 Mb. Notably, we detected 42 regions with a frequency of more than 0.2. We obtained 17 candidate genes related to body size, meat quality, and reproductive traits. Furthermore, using Fisher\'s exact test, we found 101 regions were associated with production traits by comparing high groups with low groups in terms of production traits. Of those, we identified several significant regions for production traits (P < 0.05) by association analysis, within which candidate genes including ECT2, GABRA4, and GABRB1 have been previously reported for those traits in beef cattle.
CONCLUSIONS: Our study explored ROH patterns and their potential associations with production traits in beef cattle. These results may help to better understand the association between production traits and genome homozygosity and offer valuable insights into managing inbreeding by designing reasonable breeding programs in farm animals.

Chromosomal microdeletions and microduplications have been proven to be a significant proportion of genetic factors underlying birth defects. Chromosomal microarray analysis (CMA) and next generation sequencing-based copy number variation (CNV-seq) assay have been recommended as first-tier tests for prenatal evaluation of disease-causing CNV across the genome. With the broad application of such technologies in prenatal genetic diagnosis, there is a needed to enhance the consistency in interpretation and reporting of CNV results in clinical laboratories across China. In addition, a standard guideline for prenatal analysis and reporting of regions of homozygosity (ROH) is also required. To assist the classification, interpretation and reporting of CNV/ROH, the following recommendations have been developed, which may enhance a standard application of CMA/CNV-seq techniques in prenatal genetic diagnosis.