The Impact of Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma.

Purpose: Unfortunately, treatment of patients with uveal melanoma (UM) with metastatic disease is limited. Twenty percent of patients with UM harbor a mutation in the splicing factor gene SF3B1, suggesting that aberrant spliceosome function plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome-compromised leukemic cells to these compounds.

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed.

Genome-wide methylation analysis in patients with proximal hypospadias - a pilot study and review of the literature.

In patients with proximal hypospadias, often no genetic cause is identified despite extensive genetic testing. Many genes involved in sex development encode transcription factors with strict timing and dosing of the gene products. We hypothesised that there might be recurrent differences in DNA methylation in boys with hypospadias and that these might differ between patients born small versus appropriate for gestational age.

A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds.

Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β-globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal-to-adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ-globin subunit to reverse this switch and ameliorate these symptoms.

Prediction of molecular subclasses of uveal melanoma by deep learning using routine haematoxylin-eosin-stained tissue slides.

Aims: Uveal melanoma has a high propensity to metastasize. Prognosis is associated with specific driver mutations and copy number variations, and these can only be obtained after genetic testing. In this study we evaluated the efficacy of patient outcome prediction using deep learning on haematoxylin and eosin (HE)-stained primary uveal melanoma slides in comparison to molecular testing.

The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group.

Purpose: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group.

Methods: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor.

Evaluation of Circulating Tumor DNA as a Liquid Biomarker in Uveal Melanoma.

Purpose: Uveal melanoma (UM) has a high propensity to metastasize. Prognosis is associated with specific driver mutations and copy number variations (CNVs), but limited primary tumor tissue is available for molecular characterization due to eye-sparing irradiation treatment. This study aimed to assess the rise in circulating tumor DNA (ctDNA) levels in UM and evaluate its efficacy for CNV-profiling of patients with UM.

8q Gain Has No Additional Predictive Value in Uveal Melanoma but Is Predictive for a Worse Prognosis in Patients with Uveal Melanoma.

Purpose: Gain of chromosome 8q has been associated with poor prognosis in uveal melanoma (UM), and an increase in the absolute number of 8q-copies correlated with an even shorter survival. Splicing factor 3b subunit 1 ()-mutated () tumors display structural chromosomal anomalies and frequently show a partial gain of chromosome 8qter. A recent subset of UM with early-onset metastases has been identified, prompting the investigation of the relationship between survival, 8q gain, and UM.

Uveal melanoma modeling in mice and zebrafish.

Despite extensive research and refined therapeutic options, the survival for metastasized uveal melanoma (UM) patients has not improved significantly. UM, a malignant tumor originating from melanocytes in the uveal tract, can be asymptomatic and small tumors may be detected only during routine ophthalmic exams; making early detection and treatment difficult. UM is the result of a number of characteristic somatic alterations which are associated with prognosis.

Genetic diagnostic yield in an 11-year cohort of craniosynostosis patients.

Craniosynostosis may present in isolation, 'non-syndromic', or with additional congenital anomalies/neurodevelopmental disorders, 'syndromic'. Clinical focus shifted from confirming classical syndromic cases to offering genetic testing to all craniosynostosis patients. This retrospective study assesses diagnostic yield of molecular testing by investigating prevalences of chromosomal and monogenic (likely) pathogenic variants in an 11-year cohort of 1020 craniosynostosis patients.

Clinical Relevance of Rapid FOXF1-Targeted Sequencing in Patients Suspected of Alveolar Capillary Dysplasia With Misalignment of Pulmonary Veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital lung disorder that presents shortly after birth with respiratory failure and therapy-resistant pulmonary hypertension. It is associated with heterozygous point mutations and genomic deletions that involve the FOXF1 gene or its upstream regulatory region. Patients are unresponsive to the intensive treatment regimens and suffer unnecessarily because ACDMPV is not always timely recognized and histologic diagnosis is invasive and time consuming.

Identification of Rare Variants Involved in High Myopia Unraveled by Whole Genome Sequencing.

Purpose: Myopia (nearsightedness) is a condition in which a refractive error (RE) affects vision. Although common variants explain part of the genetic predisposition (18%), most of the estimated 70% heritability is missing. Here, we investigate the contribution of rare genetic variation because this might explain more of the missing heritability in the more severe forms of myopia.

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood.

Uveal melanomas (UM) are detected earlier. Consequently, tumors are smaller, allowing for novel eye-preserving treatments. This reduces tumor tissue available for genomic profiling.

High C-Reactive Protein Levels Are Related to Better Survival in Patients with Uveal Melanoma.

Purpose: To determine whether peripheral blood leukocyte numbers and serum markers of inflammation can be used to predict which patients with primary uveal melanoma will develop metastasis.

Design: Retrospective study.

Participants: Medical records of patients with uveal melanoma (UM) who received treatment for primary UM between February 1992 and December 2020 at the Erasmus University Medical Center (Rotterdam, The Netherlands) and the Rotterdam Eye Hospital (Rotterdam, The Netherlands) were reviewed.

Is a Transcription Factor Important for Uveal Melanocyte Development and Associated with High-Risk Uveal Melanoma.

Uveal melanoma (UM) is a deadly ocular malignancy, originating from uveal melanocytes. Although much is known regarding prognostication in UM, the exact mechanism of metastasis is mostly unknown. Metastatic tumor cells are known to express a more stem-like RNA profile which is seen often in cell-specific embryonic development to induce tumor progression.

The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions.

Herein, we report on a large Polish family presenting with a classical triphalangeal thumb-polysyndactyly syndrome (TPT-PS). This rare congenital limb anomaly is generally caused by microduplications encompassing the Sonic Hedgehog (SHH) limb enhancer, termed the zone of polarizing activity (ZPA) regulatory sequence (ZRS). Recently, a pathogenic variant in the pre-ZRS (pZRS), a conserved sequence located near the ZRS, has been described in a TPT-PS Dutch family.

Kidney Organoids Are Capable of Forming Tumors, but Not Teratomas.

Induced pluripotent stem cell (iPSC)-derived kidney organoids are a potential tool for the regeneration of kidney tissue. They represent an early stage of nephrogenesis and have been shown to successfsully vascularize and mature further in vivo. However, there are concerns regarding the long-term safety and stability of iPSC derivatives.

Is Tissue Still the Issue? The Promise of Liquid Biopsy in Uveal Melanoma.

Uveal melanoma (UM) is the second most frequent type of melanoma. Therapeutic options for UM favor minimally invasive techniques such as irradiation for vision preservation. As a consequence, no tumor material is obtained.

First genome-wide association study of esophageal atresia identifies three genetic risk loci at , //, and .

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci.

Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma.

Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor , and whilst patients with such mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative of short progression-free survival (PFS < 60 months) or long PFS (PFS ≥ 60 months) for -mutated () UM patients. We collected 146 UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets.

Intrinsic Cellular Susceptibility to Barrett's Esophagus in Adults Born with Esophageal Atresia.

The prevalence of Barrett's esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux.

Genome-wide aberrant methylation in primary metastatic UM and their matched metastases.

Uveal melanoma (UM) is an aggressive intra-ocular cancer with a strong tendency to metastasize. Metastatic UM is associated with mutations in BAP1 and SF3B1, however only little is known about the epigenetic modifications that arise in metastatic UM. In this study we aim to unravel epigenetic changes contributing to UM metastasis using a new genome-wide methylation analysis technique that covers over 50% of all CpG's.

Case Report and Review of the Literature: Congenital Diaphragmatic Hernia and Craniosynostosis, a Coincidence or Common Cause?

Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that presents as either an isolated diaphragm defect or as part of a complex disorder with a wide array of anomalies (complex CDH). Some patients with complex CDH display distinct craniofacial anomalies such as craniofrontonasal dysplasia or craniosynostosis, defined by the premature closure of cranial sutures. Using clinical whole exome sequencing (WES), we found a missense variant in a patient with a left-sided congenital diaphragmatic hernia as well as sagittal suture craniosynostosis.