Bakker MK, Groenheide PJ, Vos IN
… +15 more, Lin QC, Nanninga MHA, Guzu A, Paic B, Verhoeff TA, Bekema E, Teumer A, Bülow R, Völker U, Völzke H, Grabe HJ, Kuijf HJ, Velthuis BK, Veldink JH, Ruigrok YM
Eur J Hum Genet
· 2026 Jun · PMID 41826712
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Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle...Rupture of an intracranial aneurysm (IA) can result in aneurysmal subarachnoid hemorrhage (ASAH), a severe and often fatal form of stroke. The configuration of the intracranial arteries - collectively known as the circle of Willis (CoW) - influences the risk of IA development and rupture. Although CoW variation is known to be heritable, its genetic underpinnings and contribution to IA remain poorly understood. Here, we aimed to investigate the genetic architecture of CoW variation and its potential link with IA. Using a semi-automated detection tool, we characterized the diameters, bifurcation angles, and presence of arterial segments of the CoW in 1078 participants from a population-based cohort and 682 IA patients. Composite traits capturing variation in all CoW characteristics were generated through principal component analysis. We conducted a genome-wide association study (GWAS) on these composite traits and identified four loci with suggestively significant associations. Lead single-nucleotide polymorphisms (SNPs) were located in or near the genes DPYSL2, CSMD3, TRPC6, and PKD1L2. Notably, PKD1L2 is closely related to PKD1, a gene implicated in autosomal dominant polycystic kidney disease, a connective tissue disorder that increases IA susceptibility. We observed statistically significant SNP-based heritability for the second principal component of CoW variation (heritability estimate = 0.95, standard error = 0.25). All lead SNPs demonstrated nominal association (p < 0.05) with multiple CoW characteristics and other vascular traits. Our findings highlight a substantial genetic contribution to CoW morphology and offer new insights into the molecular mechanisms underlying CoW variation and its role in IA pathogenesis.
There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey o...There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey of scope, curation, reporting and sharing practices of diagnostic laboratories performing somatic testing in Australia and New Zealand. Laboratories with accreditation (n = 41) were invited in 2023 to complete a semi-structured, 25-question interview. Responses were received for 27 laboratories (66% response rate) offering solid tumour, haematological malignancy and non-cancer services. Only 36% of laboratories offered tests capturing the full breadth of variants, from single-nucleotide variants to gene fusions. Knowledge sharing was rare, with only one laboratory submitting variant classifications to a public knowledge base. Most laboratories (96%) conducted somatic testing in oncology. Of cancer laboratories, 35% offered testing considered capable of comprehensive genomic profiling (CGP). Almost half of cancer laboratories had already adopted the 2022 ClinGen/CGC/VICC oncogenicity guidelines, and 84% were using AMP/ASCO/CAP 2017 clinical significance guidelines. Only 47% of mixed discipline cancer laboratories reported biomarkers such as tumour mutational burden, with wide variation in reporting of matched therapy options. Our study has generated a unique overview of somatic laboratory practices in the region, and areas for global standardisation in somatic molecular testing and reporting. We also provide a model for practice and guideline uptake assessment, for application by other country-wide networks. This is particularly relevant in anticipation of CGP mainstreaming, with the increasing complexity of sequencing interpretation for laboratories and clinicians.
Farooq M, Bruun GH, Sarusie MVK
… +12 more, Kessel L, Akhtar H, Abdullah U, Ali Z, Shah SA, Ali N, Anjum I, Doktor TK, Andresen BS, Baig SM, Larsen LA, Grønskov K
Eur J Hum Genet
· 2026 May · PMID 41807736
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Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined wit...Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.
Hereditary cancer syndromes are among the most common inherited disorders and contribute to nearly 10% of solid tumours. While genetic testing is now central to diagnosis, surveillance, and cascade prevention, its impact...Hereditary cancer syndromes are among the most common inherited disorders and contribute to nearly 10% of solid tumours. While genetic testing is now central to diagnosis, surveillance, and cascade prevention, its impact is constrained by the persistent challenge of variants of uncertain significance (VUS), which comprise almost 40% of reported hereditary cancer syndrome-associated variants in ClinVar. These unresolved classifications undermine the interpretive power of testing, limiting its translational and preventive potential. In this review, we examine the foundations of variant interpretation, the role of expert-guided specifications, and emerging methods for VUS reclassification, including population-level data, RNA- and protein-based functional assays, computational predictors, and long-read sequencing. We further highlight how systematic re-evaluation structures and curation infrastructures translate new evidence into clinical practice. We conclude with an outlook on future directions to reduce the burden of VUS and increase the clinical utility of hereditary cancer syndrome testing.
Cohen RJ, McWhirter R, Newett L
… +3 more, Colonna E, Hermes A, Brown A
Eur J Hum Genet
· 2026 Jun · PMID 41807734
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Indigenous communities are under-represented in genomics research, contributing to inequitable health-related knowledge, outcomes, and benefits. Under-representation reflects enduring consequences of colonial research pr...Indigenous communities are under-represented in genomics research, contributing to inequitable health-related knowledge, outcomes, and benefits. Under-representation reflects enduring consequences of colonial research practices that have engendered cultural, ethical, legal, and social (CELS) concerns among communities. Researchers must understand, navigate, and address these in their research practices. This study aimed to identify and synthesise CELS considerations to inform Indigenous genomics research practices. A systematic scoping review was conducted, including peer-reviewed papers on genomics that discussed cultural, ethical, legal, or social matters relevant to Indigenous Peoples globally; available in full-text and in English. Inductive content analysis using NVivo 12 Plus was undertaken to identify CELS considerations and develop content categories, with papers coded to multiple categories where relevant. As of May 2024, 186 papers were identified for inclusion: n = 70 (38%) included cultural, n = 91 (49%) ethical, n = 49 (26%) legal, and n = 125 (67%) social considerations. Cultural considerations included cultural harm, significance of blood, and the need to integrate Indigenous knowledges. Ethical considerations included consent, data access and sharing, privacy, and confidentiality. Legal considerations included laws protecting Indigenous interests, control of genomic samples and data, biovalue and DNA as a commodity, genetic discrimination, and the use of genomic data in constructing and defining racial identity. Social considerations included collective decision-making, genetic determinism, and stigmatisation, and the importance of contextualising findings within wider social determinants of health frameworks. Overall, researchers need to understand, navigate, and address CELS considerations of relevance to Indigenous Peoples to build trust, promote inclusion, and support equitable benefit-sharing in genomics research.
Jaramillo Oquendo C, Ferraro F, Wai HA
… +14 more, Ferrao H, van der Linde H, Karelioti E, Tseng L, Dhillon H, Holt S, Bunyan DJ, Donker Kaat L, van Dooren M, Zhou J, Ennis S, Holloway JW, van Ham TJ, Baralle D
Eur J Hum Genet
· 2026 Jun · PMID 41807732
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Splice-disrupting variants are estimated to account for one-third of disease-causing variants, yet many remain underrepresented in clinical databases due to limitations in detecting splicing changes beyond canonical spli...Splice-disrupting variants are estimated to account for one-third of disease-causing variants, yet many remain underrepresented in clinical databases due to limitations in detecting splicing changes beyond canonical splice sites. Short-read RNA sequencing (RNA-seq) has proved to be a valuable complement in clinical practice to address this gap, however, the added value of long-read RNA-seq is unclear. We evaluated the potential of PacBio long-read RNA-seq to detect pathogenic splicing events in rare disorders, comparing its performance to short-read RNA-seq. Participants from the UK (n = 23) and the Netherlands (n = 2) with suspected splice-altering variants underwent long-read RNA-seq following the Kinnex full-length RNA protocol. HiFi reads from the Revio instrument were processed using the Read Segmentation and Iso-Seq workflow and then classified and filtered using Pigeon. Detection of disease genes was comparable with short reads, with fibroblast capturing more transcripts overall. Novel isoforms accounted for ~14% of detected transcripts in both tissues, increasing following cycloheximide treatment in fibroblasts and decreasing following globin depletion in blood. Transcript abundance estimates showed strong concordance between short- and long-read platforms (Pearson r = 0.86 and 0.61 in blood and fibroblasts, respectively). LRS captured 21 confirmed known events, and revealed additional transcript-level effects in eight cases. This included intron retention, multiple exon skipping, leaky splicing, variant phasing, and isoform switching. These results demonstrate that long-read RNA-seq enhances detection and interpretation of clinically relevant splicing events, supporting its integration into diagnostic workflows for rare diseases.
Marin V, Lannes H, Dumont V
… +6 more, Thevenon J, Baux D, Roux AF, Lasseaux E, Pennamen P, Lebreton L
Eur J Hum Genet
· 2026 May · PMID 41795033
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In the era of rapidly accumulating genomic data, largely driven by the broad use of whole-genome sequencing (WGS) in clinical settings, interpreting lesser-known genes with varied phenotypes remains challenging. PubMatch...In the era of rapidly accumulating genomic data, largely driven by the broad use of whole-genome sequencing (WGS) in clinical settings, interpreting lesser-known genes with varied phenotypes remains challenging. PubMatcher is a new tool that simplifies bibliographic research for multiple genes at once and grants quick and easy access to relevant gene information. It helps users efficiently identify potential genotype-phenotype associations using PubMed complemented by additional data. By significantly reducing analysis time, PubMatcher supports the interpretation of novel or under-documented genes. Freely available for academic and non-commercial use, PubMatcher is a user-friendly and efficient solution for researchers, clinical scientists and clinical geneticists working on pan-genomics analyses.
Abnormal RNA splicing is an underrecognized driver of pathogenicity in germline TP53 - the cause of Li-Fraumeni syndrome (LFS). We re-evaluated exonic single-nucleotide variants (SNVs) that yield missense or synonymous c...Abnormal RNA splicing is an underrecognized driver of pathogenicity in germline TP53 - the cause of Li-Fraumeni syndrome (LFS). We re-evaluated exonic single-nucleotide variants (SNVs) that yield missense or synonymous changes for spliceogenic effects by integrating SpliceAI prediction, in-vitro minigene assays, and analysis of tumor RNA-seq from TCGA, and assessed genotype-phenotype correlations using clinical data from multiple databases and national registries. We identified 58 spliceogenic exonic SNVs (SE-SNVs) across the TP53 gene (40 missense, 18 synonymous). Experimental validation confirmed aberrant splicing for 15 out of 17 tested variants, most often through cryptic splice-site activation that introduced frameshifts and premature termination. Clinically, carriers of SE-SNVs previously considered as mild or of low-pathogenicity by protein-based assays showed earlier onset and LFS-signature cancers, indicating that splicing disruption can override amino-acid effects. The recurrent c.375 G > A (p.(Thr125 = )) showed heterogeneous effect: with both childhood/adolescent and adult onset, consistent with partial, variable retention of canonical splicing. These data reveal a substantial burden of spliceogenic pathogenicity in TP53 and strong support integrating splicing prediction, functional validation, and transcript-level evidence into variant interpretation and risk stratification in LFS.
Individuals with hereditary cancer syndromes (HCS) face significant healthcare challenges, as they require lifelong surveillance for a multitude of at-risk organs. Despite the existence of HCS programs, literature has no...Individuals with hereditary cancer syndromes (HCS) face significant healthcare challenges, as they require lifelong surveillance for a multitude of at-risk organs. Despite the existence of HCS programs, literature has not elucidated the patient perspective of living with an HCS and the care journey. This study aimed to inform clinical practice by exploring the care experiences of HCS patients. HCS patients were purposely sampled from cancer/genetic clinics across three Canadian provinces to reflect demographic and clinical variations. Data collection included qualitative, semi-structured interviews. Analysis used interpretive descriptive methodology. Seventy-three participants were interviewed (39 Hereditary breast and ovarian cancer syndrome, 34 Lynch syndrome; 51 females, 21 males, 1 gender-diverse; aged 25-80). Participants described a sense of disorientation after their HCS diagnosis, with a sense of navigating a road without a map. These feelings emerged from the "fragmentation" of their care, bodies, and information from healthcare practitioners. Consequently, participants described experiencing uncertainty and distress, and desired care integration in the form of consistent, knowledgeable practitioners and a holistic approach to care. Key timepoints were revealed where increased psychological support may be required: following HCS diagnosis, when obtaining imaging results, and when undergoing risk-reducing surgery. This study highlights the need for a comprehensive, person-centered approach to HCS management.
Secondary findings (SF) identified in massive parallel sequencing raise important clinical and healthcare related questions. To get an overview on current practices of European healthcare providers (HCP), we conducted a...Secondary findings (SF) identified in massive parallel sequencing raise important clinical and healthcare related questions. To get an overview on current practices of European healthcare providers (HCP), we conducted a cross-sectional survey study among 39 stakeholders-predominantly senior medical and laboratory geneticists-from 15 European countries participating in the European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS). Respondents reported considerable heterogeneity in SF management and reporting, even within countries. While 31% of responding HCP return findings from all 81 genes on the American College of Medical Genetics and Genomics (ACMG) recommended SF list version 3.2, 41% restrict SF disclosure, often excluding genes associated with cardiological or metabolic disorders or with limited clinical actionability. A further 26% do not report ACMG-listed SF at all. Notably, 70% of HCP also assess additional cancer-predisposition genes beyond the ACMG list, using in-house gene lists or national guidelines. Most HCP restrict reporting to (likely) pathogenic variants (90%) and find SF in less than 5% of genetic analyses (59%). Consent procedures and patient information practices varied, with most HCP employing opt-in consent models and genetic counselling primarily delivered by medical geneticists and genetic counsellors. Major institutional challenges raised by participants, include lack of harmonised guidelines, concerns about patient anxiety, and insufficient resources for follow-up care. The findings of this study highlight the need for robust, evidence-based European guidelines to ensure clinically relevant and patient-centred SF management.
Brunelle P, Jourdain AS, Escande F
… +12 more, Audebert-Bellanger S, Bouquillon S, Cormier-Daire V, Desdoits A, Lacombe D, Molin A, Gruchy N, Touraine R, Van Gils J, Ghoumid J, Thomes L, Petit F
Eur J Hum Genet
· 2026 May · PMID 41776344
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Limb malformations are paradigmatic of altered gene regulation in human disease. Nail-Patella Syndrome (NPS) is a rare condition characterized mainly by skeletal defects, glomerulonephritis and glaucoma, with variable ex...Limb malformations are paradigmatic of altered gene regulation in human disease. Nail-Patella Syndrome (NPS) is a rare condition characterized mainly by skeletal defects, glomerulonephritis and glaucoma, with variable expressivity. NPS is caused by the haploinsufficiency or loss-of-function of LMX1B, which encodes a transcription factor involved in limb dorsalization, in the renal glomerular filtration barrier and the anterior segment of the eye. The dorsal expression of LMX1B in the developing limbs is under the control of LMX1B autoregulatory modules (LARMs), which are non-coding cis-regulatory elements (CREs) with a limb-specific enhancer activity. Here, we describe the regulatory landscape and report regulatory anomalies at the LMX1B locus in four families, including the deletion of a CRE, two structural variations disrupting the CRE-promoter interaction, and a 5'UTR variant causing an upstream open reading frame (ORF). Molecular mechanisms involving the non-coding genome can have a tissue-specific impact on gene expression, resulting in incomplete forms of the syndrome, and sometimes modifying its classical mode of inheritance. While approximately 95% of individuals with NPS carry pathogenic variants in the coding regions of LMX1B, non-coding alterations explain the remaining cases. This work highlights the importance of genomic diagnosis (gene ORF versus CRE alteration) for precision medicine and genetic counselling in rare diseases.
Cancer Predisposition Syndromes (CPS) are heritable genetic conditions associated with an increased risk of developing various cancers throughout life. While early identification and tumour surveillance can improve outco...Cancer Predisposition Syndromes (CPS) are heritable genetic conditions associated with an increased risk of developing various cancers throughout life. While early identification and tumour surveillance can improve outcomes, CPS are often underdiagnosed in clinical practice. To evaluate clinicians' perspectives and identify barriers to CPS identification and care across Europe, we conducted the SCOPE study: a three-part cross-sectional survey of paediatric haematology/oncology professionals, followed by a modified Delphi consensus process with members of the SIOP Europe Host Genome Working Group. A total of 185 paediatric oncologists from 22 countries participated in the survey. More than 40% of participants reported low or uncertain confidence across different CPS-related tasks, particularly in counselling families (64.3%) and interpreting germline genetic findings (57.3%). Access to clinical geneticists and dedicated CPS clinics were predictors of higher confidence for some domains, while individual experience and institutional patient volume had limited influence. Regular use of universal CPS screening tools was low (42.3%), with most clinicians relying on personal judgement rather than structured criteria. The most cited barriers were lack of screening guidelines (57%) and difficulties in interpreting results (35.1%). Regular training and workshops, availability of genetic counsellors or educators for patient support, and patient-friendly education material were most cited as areas of improvement. The Delphi process led to three recommendations: (1) improve clinician training and communication strategies, (2) integrate CPS screening into standard treatment plans, and (3) develop accessible, patient-centred educational materials. These recommendations highlight opportunities to enhance CPS care through structured support, interdisciplinary collaboration, and systematic screening approaches.
Cascade screening enables effective secondary prevention and early treatment for Thoracic Aortic Disease (TAD) and increases survival. Despite guideline recommendations, the uptake of screening remains low. This study in...Cascade screening enables effective secondary prevention and early treatment for Thoracic Aortic Disease (TAD) and increases survival. Despite guideline recommendations, the uptake of screening remains low. This study investigated individual and organisational barriers to screening participation. We performed clinician and public focus groups (n = 19 participants across 5 sessions), semi-structured interviews (4 clinicians) and a national patient/relative survey (n = 242 responses: 71 probands, 171 relatives). Behavioural theories guided data interpretation and thematic analysis. Data collection explored motivations, psychological and practical burdens, communication dynamics and attitudes towards screening and Decision Support Tools (DSTs). A national survey of TAD patients and their families provided quantitative context on demographics, genetic testing uptake and involvement in shared decision-making. Thematic analysis using the framework approach was applied to qualitative data. Qualitative analysis of focus groups, interviews and a national patient/relative survey (n = 242) identified significant barriers to TAD cascade screening, including fragmented services, inconsistent clinician knowledge and patient confusion regarding genetic testing pathways. Survey data showed low genetic testing uptake (47% survivors; 44% and 21% for first- and second-degree relatives). Conversely, key facilitators for a DST included user-friendliness, multi-modal accessibility, clear risk/benefit communication and the inherent value of reassurance with professional endorsement from healthcare providers. These would directly address observed psychological and practical burdens. Patient and family engagement in TAD cascade screening faces complex barriers, including psychological burdens and systemic issues, resulting in a substantial shared decision-making gap. User-centric, multi-modal Decision Support Tools, supported by enhanced clinician education and structured family communication, are vital for effective TAD prevention.
Patients with colorectal cancer (CRC) and Lynch syndrome (LS) have elevated cancer risks and require personalized treatment and targeted surveillance. At-risk relatives can also benefit from preventive measures. However,...Patients with colorectal cancer (CRC) and Lynch syndrome (LS) have elevated cancer risks and require personalized treatment and targeted surveillance. At-risk relatives can also benefit from preventive measures. However, LS remains largely undiagnosed. Integration of universal tumor screening (UTS) with mainstream genetic testing in patients with CRC has been recommended, but implementation of this approach remains inconsistent. This scoping review mapped evidence on barriers and facilitators in diagnostic pathways that integrate UTS and mainstream genetic testing for LS in CRC. A search of MEDLINE, Scopus, CINAHL and PsycINFO was conducted, and five articles were selected. Barriers and facilitators were mapped to the Theoretical Domains Framework (TDF). The most frequently mapped domains were Environmental Context and Resources (in 5/5 articles) Social/Professional Role and Identity, Beliefs about Consequences, Social Influences, and Behavioral Regulation (all in 4/5 articles). Barriers included insufficient clinician education, difficulties in navigating consent processes and interpreting testing results, and perceived lack of evidence demonstrating the benefit of genetic testing. Unclear and conflicting perceptions among different professional groups about who should be responsible for essential components of genetic testing and follow-up also emerged. Social Influences such as strong leadership, collaboration, and networked support from "champions" acted as key facilitators. Mechanisms of Behavioral Regulation, including audit, feedback, and ongoing education, as well as appropriate resourcing, were identified as essential for sustaining practice change. Future studies could usefully explore patients' views and preferences regarding novel diagnostic pathways for LS in CRC that align UTS and mainstream genetic testing, as well as strategies developed and implemented in low-resource settings.
Comprehensive genomic profiling (CGP) has significantly advanced cancer genomics by enabling broad detection of clinically relevant genomic alterations across diverse cancers. In the context of BRCA1/2, CGP has expanded...Comprehensive genomic profiling (CGP) has significantly advanced cancer genomics by enabling broad detection of clinically relevant genomic alterations across diverse cancers. In the context of BRCA1/2, CGP has expanded analysis beyond conventional testing for hereditary breast and ovarian cancer (HBOC), thereby identifying otherwise unrecognized variants. Nevertheless, the high prevalence of variants of uncertain significance (VUS) remains a major obstacle to clinical implementation. To address this challenge, we analyzed 2172 CGP tests performed at Hiroshima University Hospital and affiliated institutions in Japan. BRCA1/2 VUS identified through CGP were systematically prioritized using an integrative framework combining in silico prediction and functional evidence. From 526 BRCA1/2 variants, 153 were classified as VUS. Our variant prioritization filter based on ten in silico predictors narrowed these to 10 candidates, including two splice-site and eight missense variants, most of which were concordant with prior functional studies. Among these, the significance of BRCA2:c.67 G > C (p.D23H, NM_000059.4) had remained unclear. Functional analysis demonstrated exon 2 skipping consistent with loss of function, and clinical observations from two patients carrying this variant showed that therapeutic responses aligned with the biology of homologous recombination deficiency. These findings present a proof-of-concept framework for prioritizing and interpreting BRCA1/2 VUS detected in real-world CGP testing. By integrating multiple in silico predictors with functional evidence, this approach enables systematic prioritization and interpretation of BRCA1/2 VUS and may be broadly applicable to variant assessment in hereditary cancer predisposition genes.
Newborn screening (NBS) is an effective measure of secondary prevention. The application of genomic sequencing in population-based screening would enable further expansions of the NBS disease panel and a genomic NBS (gNB...Newborn screening (NBS) is an effective measure of secondary prevention. The application of genomic sequencing in population-based screening would enable further expansions of the NBS disease panel and a genomic NBS (gNBS). The selection of NBS target diseases is still based on the Wilson and Jungner screening principles from 1968, which are considered incomplete, particularly for an extension towards gNBS. The present work aims to establish a multi-dimensional framework for future gNBS programs. An interdisciplinary expert panel comprising researchers from pediatric and adolescent medicine, human genetics, ethics, medical psychology, law, and patient representatives used a nominal group technique-like multi-stage consensus process to define criteria for gNBS, considering ethical, legal, and social implications, medical aspects, and patient perspectives. Overall, 18 criteria were developed, clustered into four subcategories: I. Clinical criteria (characteristics of the target disease); II. Diagnostic criteria (requirements of the test); III. Therapeutic-interventional criteria (prerequisites of the intervention); IV. Program management criteria (requirements of the program). Subcategories I-III define selection criteria for target diseases, subcategory IV defines criteria for how to establish and manage the program. In conclusion, this multi-dimensional framework serves as a well-balanced basis for developing thoroughly revised and internationally accepted consensus screening criteria.