Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders.

Background: A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform on the underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, the detection of these episignature requires the use of indirect methylation profiling methodologies.

Healthcare professionals' experiences with expanded noninvasive prenatal screening: challenges and solutions.

Genome-wide non-invasive prenatal cell-free DNA screening (NIPT) can lead to the early detection of important health-related information for the fetus and pregnant woman. However, the expanding scope of screening heightens information complexity and creates challenges for clinical interactions. This study explored Belgian healthcare professionals' experiences to identify challenges and solutions to expanded NIPT in practice.

Full characterization of unresolved structural variation through long-read sequencing and optical genome mapping.

Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full.

Multiple paralogues and recombination mechanisms contribute to the high incidence of 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder.

Perspectives of preimplantation genetic testing patients in Belgium on the ethics of polygenic embryo screening.

Research Question: What are the perspectives of preimplantation genetic testing (PGT) patients in Belgium on the ethics of PGT for polygenic risk scoring (PGT-P)?

Design: In-depth interviews (18 in total, 10 couples, 8 women, n = 28) were performed with patients who had undergone treatment with PGT for monogenic/single-gene defects (PGT-M) or chromosomal structural rearrangements (PGT-SR) between 2017 and 2019 in Belgium. Participants were asked about their own experiences with PGT-M/SR and about their viewpoints on PGT-P, including their own interest and their ideas on its desirability, scope and consequences. Inductive content analysis was used to analyse the interviews.

Polygenic embryo screening: quo vadis?

Recently, the use of polygenic risk scores in embryo screening (PGT-P) has been introduced on the premise of reducing polygenic disease risk through embryo selection. However, it has been met with extensive critique: considered "technology-driven" rather than "evidence-based", concerns exist about its validity, utility, ethics, and societal effects. Its scientific foundations and criticisms thus need to be carefully considered.

Comprehensive Recommendations for the Clinical Management of Pregnant Women With Noninvasive Prenatal Test Results Suspicious of a Maternal Malignancy.

In this article, we defined comprehensive recommendations for the clinical follow-up of pregnant women with a malignancy-suspicious NIPT result, on the basis of the vast experience with population-based NIPT screening programs in two European countries complemented with published large data sets. These recommendations provide a tool for classifying NIPT results as malignancy-suspicious, and guide health care professionals in structured clinical decision making for the diagnostic process of pregnant women who receive such a malignancy-suspicious NIPT result.

Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder.

Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis.

A novel method for the isolation of single cells mimicking circulating tumour cells adhered on Smart Bio Surface slides by Laser Capture Microdissection.

In recent years, the importance of isolating single cells from blood circulation for several applications, such as non-invasive tumour diagnosis, the monitoring of minimal residual disease, and the analysis of circulating fetal cells for prenatal diagnosis, urged the need to set up innovative methods. For such applications, different methods were developed. All show some weaknesses, especially a limited sensitivity, and specificity.

Should non-invasive prenatal testing (NIPT) be used for fetal sex determination? Perspectives and experiences of healthcare professionals.

Non-invasive prenatal testing (NIPT) can not only accurately detect early in pregnancy the presence of chromosomal abnormalities but also fetal sex. However, whether fetal sex should be reported after performing NIPT is ethically contentious. In Belgium, NIPT is practically fully reimbursed and offered to all pregnant women as a first-tier screening.

Gollop-Wolfgang Complex Is Associated with a Monoallelic Variation in .

Gollop-Wolfgang complex (GWC) is a rare congenital limb anomaly characterized by tibial aplasia with femur bifurcation, ipsilateral bifurcation of the thigh bone, and split hand and monodactyly of the feet, resulting in severe and complex limb deformities. The genetic basis of GWC, however, has remained elusive. We studied a three-generation family with four GWC-affected family members.

"Are we not going too far?": Socio-ethical considerations of preimplantation genetic testing using polygenic risk scores according to healthcare professionals.

The recent introduction of polygenic risk scores within preimplantation genetic testing (PGT-P) has been met with many concerns. To get more insights into the perspectives of relevant stakeholders on the socio-ethical aspects of PGT-P, an interview study with 31 healthcare professionals involved in reproductive medicine and genetics in Europe and North-America was performed. Healthcare professionals in our study were concerned that PGT-P was going too far in terms of selection, with regards to both medical conditions and non-medical traits.

Cell-free DNA methylome analysis for early preeclampsia prediction.

Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE.

What helps define outcomes in persistent uninterpretable non-invasive prenatal testing: Maternal factors, fetal fraction or quality scores?

Objectives: To assess maternal characteristics and comorbidities in patients with persistent uninterpretable non-invasive prenatal testing (NIPT) and to evaluate the association with adverse pregnancy outcome in a general risk population.

Methods: A retrospective cohort study (July 2017-December 2020) was conducted of patients with persistent uninterpretable NIPT samples. Maternal characteristics and pregnancy outcomes were compared with the general Belgian obstetric population.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS).

Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles.

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS).

Limitations, concerns and potential: attitudes of healthcare professionals toward preimplantation genetic testing using polygenic risk scores.

Preimplantation genetic testing using polygenic risk scores (PGT-P) has recently been introduced. However, PGT-P has been met with many ethical concerns. It is therefore important to get insights into the perspectives of stakeholders regarding PGT-P.

Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia.

22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.