Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

in Human Genomics (2023), 17(1), 39

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main ... [more ▼]

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques. [less ▲]

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

in Genetics in Medicine (2023), 25(4), 100018

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a ... [more ▼]

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. [less ▲]

The cardiometabolic depression subtype and its association with clinical characteristics: The Maastricht Study

in Journal of Affective Disorders (2022)

Programme Démence Prévention (pdp ): A Nation-Wide Programme for Dementia Prevention in Luxembourg

Poster (2020, April)

Objectives: To implement a multi-year nation-wide programme, by the means of a personalised lifestyle intervention, to prevent or to delay cognitive decline that can contribute to development of dementia ... [more ▼]

Objectives: To implement a multi-year nation-wide programme, by the means of a personalised lifestyle intervention, to prevent or to delay cognitive decline that can contribute to development of dementia in Luxembourg. Methods: Participants with mild cognitive impairment, referred to the programme by their treating physician, undergo an extensive cognitive evaluation by a neuropsychologist on relevant neuropsychological domains as well as a structured dementia risk factor assessment. Based on these assessments, individualised lifestyle interventions are offered by diverse national partners involved in the programme, thus filling a gap of not yet reimbursed services in the Luxemburgish healthcare system. After the personalised lifestyle interventions, each participant will undergo a neuropsychological follow-up in order to re-evaluate his/her health status in terms of cognition. Results: We established a participant-centred national network by presenting the programme on many outreach events and efficient stakeholder communication. The network raises the awareness of dementia prevention in the Luxembourgish population, fosters interdisciplinary communication between individual medical and non-medical healthcare professionals and allows for a successful recruitment of the target population. Moreover, we collect information about adherence to the suggested lifestyle changes, as well as the effectiveness of our interventions in reducing risk factors contributing to the onset of dementia. Conclusions: We provide evidence for the feasibility of the implementation of a nation-wide dementia prevention programme including diverse partners offering personalised lifestyle interventions, which are easily transferrable to other countries. Future results from this programme may also help to integrate prevention interventions into the regular healthcare system. [less ▲]

The Human Phenotype Ontology in 2017

in Nucleic Acids Research (2016)

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components ... [more ▼]

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. [less ▲]