Difficulties of sharing information about genetic risks, for medical purposes, with family members are well known to patients with rare genetic diseases and healthcare professionals. To understand the mechanisms underlying the difficulties associated with the family disclosure of genetic risk (FDGR) process, an online questionnaire survey was designed in collaboration with French patient associations, healthcare professionals and academics. 595 patients with various rare diseases, or their relatives, who had an experience of FDGR, reported 685 FDGR events. Using hierarchical clustering on the principal components (HCPC) of a multiple correspondence analysis (MCA), these 685 experiences were divided into three clusters, representing 347 (Cluster 1 50.7%), 175 (Cluster 2 25.5%) and 163 (Cluster 3 23.8%) FDGR events, respectively. In cluster 1, the FDGR events described were considered generally satisfactory. In cluster 2 and cluster 3 (approximately 50% of FDGR), the FDGR events described were considered unsatisfactory, both in terms of information transmission and psychosocial damage, mainly due to a poor understanding of the information to be conveyed and/or low motivation, particularly in families experiencing relationship difficulties. However, other factors, such as certain characteristics of the disease or the type of healthcare professional involved in the process, do not appear to differ significantly between the three clusters. Our results, obtained through a collaborative approach, provide a basis for the collective development of tools (i) aimed at improving patients’ understanding of genetic information and their motivation to disclose it to family members, but if this proves impossible or too difficult, (ii) to delegate disclosure to healthcare professionals.
A developmental language disorder (DLD) is a neurobiological condition characterized by impaired language development despite adequate linguistic input and normal intelligence. The role of monogenic causes in the pathogenesis of DLD is largely unknown and diagnostic genetic testing is rarely offered. This study assessed the diagnostic yield of genome sequencing in severe DLD and investigated the underlying genetic foundations. We designed a prospective cohort study involving trio-based genome sequencing in 25 individuals (aged 3-25 years) with severe DLD, no intellectual disability (non-verbal IQ ≥ 70), no autism spectrum disorder diagnosis and no first-degree family history of DLD or neurodevelopmental disorders. (Likely) pathogenic variants were found in nine of 25 individuals, reflecting a molecular diagnostic yield of 36%. The genetic causes were diverse and involved seven autosomal dominant disorders, one autosomal recessive disorder, and one sex chromosome aneuploidy. In seven individuals, the disease-causing variant occurred de novo. All identified (likely) pathogenic variants were located in genes or loci that have been previously implicated in neurodevelopmental disorders with variable clinical presentations. Importantly, the genetic diagnosis provided actionable insights for counselling and clinical follow-up for all nine individuals. This study reveals a high prevalence of rare (mainly de novo) genetic variants in individuals with severe and sporadic DLD, and demonstrates extensive molecular overlap with other neurodevelopmental disorders. Our results support the implementation of routine trio-based genetic testing in individuals with severe and sporadic DLD.
The increasing complexity of genomic medicine has intensified the emotional, ethical, and relational demands placed on genetic counselling professionals. In response to these demands, genetic counselling supervision has been increasingly recognised as a core component of safe and sustainable practice. However, its implementation across Europe remains uneven, and empirical evidence on feasible and acceptable supervision models in clinical settings is limited. This study reports a mixed-methods pilot evaluation of a narrative-informed, group-based genetic counselling supervision programme implemented within Portuguese public genetic services. This is a foundational component of the first phase of the MAG-SUDOE project, a transnational initiative supported by the Interreg SUDOE programme aimed at developing a joint supervision solution for genetic counselling professionals in Portugal, Spain, and France. Eight genetic healthcare professionals were recruited, and seven completed the intervention. Feasibility and acceptability were examined through participation and attendance rates, session evaluations, and assessment of the supervisory working alliance. Preliminary impact was explored using self-report measures of psychological well-being and perceived counselling quality, complemented by qualitative data from written narratives, semi-structured interviews, and a final focus group. The programme demonstrated high feasibility, with strong engagement and completion despite clinical workload constraints, and high acceptability, reflected in positive session evaluations and strong supervisory working alliance. Qualitative findings indicated that participants experienced supervision as a safe and reflective space that reduced isolation, supported emotional regulation, and enhanced reflective awareness. Overall, this pilot study provides promising indications of benefit for reflective practice and professional well-being, supporting its further adaptation and implementation within a transnational European framework.
Pathogenic CHD8 variants cause autosomal dominant 'Intellectual developmental disorder with autism and macrocephaly' (IDDAM) and are amongst the most common monogenic causes of autism. The clinical significance of CHD8 missense variants (MVs) frequently remains uncertain. Systematically applying ACGS/ACMG guidelines to 36 CHD8 MVs in 39 affected patients, only two variants were classified likely pathogenic (LP), with the remaining 34 classified variants of uncertain significance (VUS). We subclassified the variants according to posterior probability of pathogenicity (PPP), with 14 being at least tepid VUS (PPP ≥ 50%). Comprehensive phenotypic analysis revealed no discernible clinical differences between individuals carrying at least tepid VUS and others, offering no additional insight for variant classification. EpiSign™ testing revealed a CHD8-IDDAM episignature, as previously detected in patients with truncating/null variants, in 11 cases, allowing reclassification of 8 VUS (all previously classified at least tepid) as LP. Molecular modelling indicated that disease-causing (LP/P) CHD8 MVs are concentrated in structured and/or functional protein domains. Compared to truncating/null variants, disease-causing MVs were less often associated with attention issues and macrocephaly, but clinical features were otherwise similar. Additionally, three disease-causing MVs were inherited from unaffected/mildly affected parents. Overall, we show that determining the clinical significance of CHD8 MVs is challenging, even with detailed clinical information, but that incorporating episignature analysis increases diagnostic yield. Further, our results indicate that CHD8 MVs are likely to act via a loss-of-or reduced function mechanism. These findings reveal the importance and complexity of interpreting CHD8 MVs and will improve the diagnosis and understanding of CHD8-related disorders.
Accessibility of rapid genomic sequencing (rGS), including rapid whole-exome sequencing (rWES) and rapid whole-genome sequencing (rWGS), is transforming care in neonatal intensive care units (NICUs) by enabling timely and precise diagnoses of genetic disorders with high diagnostic yield and significant impact on clinical management. However, determining which infants should undergo sequencing remains a major challenge, particularly in settings with limited genetic expertise and poor access to genomic resources. Currently, no single strategy optimizes diagnostic yield, equity, feasibility, and cost across all settings. We conducted a structured literature review to evaluate patient selection approaches for genomic sequencing in the NICU and synthesized findings from major studies comparing various inclusion-based and exclusion-based approaches. Across 39 included studies, all except one utilized phenotype-driven inclusion criteria based on, for example, congenital anomalies, neurological manifestations, multisystem disease, or unexplained critical illness, while only one study employed a predominantly exclusion-based, genotype first strategy. Studies were conducted primarily in tertiary or high-resource NICUs, highlighting ongoing disparities in access to genomic testing and specialist expertise. Future research should focus on prospective comparisons of selection frameworks and the development of scalable implementation models that support equitable genomic care in NICU populations.
Whole-genome sequencing (WGS) projects for rare disease diagnosis typically yield a diagnostic rate of 25-41%, depending on the methods for patient selection and the extent of prior genetic testing. The Scottish Genomes Partnership (SGP) is a collaborative programme using genome sequencing to diagnose rare disease patients with presumed monogenic aetiology in the Scottish NHS. Within SGP, short-read sequencing (SRS) had previously achieved a diagnostic rate of 23% in affected families. To increase diagnostic yield, we applied Oxford Nanopore Technologies (ONT) long-read sequencing (LRS) to a cohort of 24 SGP families (74 individuals) that remained undiagnosed after SRS-based SNV/indel analysis. We also retrospectively reviewed SRS-derived structural variant (SV) calls to assess whether LRS results could have been detected in SRS data. After quality, rarity, panel-based and inheritance-based filtering, 392 candidate SVs were retained across de novo, homozygous recessive, compound heterozygous and X-linked inheritance models, of which 8 overlapped PanelApp diagnostic-grade "green" genes. Pathogenic or likely pathogenic de novo SVs were identified in 3 of 24 families: an AUTS2 inversion, a DLX5/6 locus inversion, and an FN1 deletion. All three SVs were independently confirmed by retrospective SRS re-analysis using SVRare. These findings demonstrate that LRS-based SV analysis, supported by orthogonal SRS re-analysis, can resolve clinically significant SVs in families who remain unsolved after standard rare disease testing.
As genomic newborn screening (gNBS) progresses toward broader implementation, questions arise regarding conditions to include on first-tier sequencing panels. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common monogenic disorder worldwide, is inconsistently screened in Europe despite its established role in neonatal hyperbilirubinemia and hemolytic crises. Using data from the Belgian BabyDetect pilot, one of the first European programs to include the evaluation of genomic and biochemical newborn screening in the same cohort, together with international evidence, we assessed the readiness of G6PD deficiency for inclusion in gNBS. In BabyDetect, genomic screening identified 94 newborns carrying pathogenic or likely pathogenic G6PD variants, including 17 neonates not detected by routine biochemical screening, demonstrating the complementary value of sequencing. However, identifying additional moderately deficient infants introduces uncertainty regarding penetrance, follow-up burden, healthcare impact and cost-effectiveness. Screening readiness was evaluated using an adapted NEXUS 2015 semi-quantitative framework, where G6PD deficiency scored 17/21, reflecting strong clinical benefit, high feasibility and ethical favorability, with moderate analytic validity, population impact, and evidence strength. Published economic modeling suggests the principal value of screening derives from reducing severe hyperbilirubinemia complications and later hemolytic crises, with additional benefits from improved pharmacovigilance and risk mitigation for subsequent siblings within affected families. Given the minimal marginal cost of adding G6PD to existing gNBS workflows, available evidence indicates that G6PD deficiency is well-suited for inclusion in gNBS when paired with confirmatory testing and proportionate, pediatric-led follow-up.
Interest in the potential of population-based genomic sequencing is growing. However, integrating a large-scale screening program into an already complex healthcare system is challenging. The implementation of gNBS needs a thorough understanding of the process. The purpose of this study is to investigate how gNBS can be integrated into the Australian health system and delivered at scale. Embedded within the BabyScreen+ study, we utilised a research design informed by process mapping and phenomenology. Fifty-one semi-structured interviews with parents (n = 33), healthcare providers (n = 15), and BabyScreen+ study team members (n = 8) were conducted. Additionally, we analysed the operational team meeting minutes. A baseline process map, developed in consultation with team members, consisted of six stages: 1. Raising awareness of the screening program; 2. Offer; 3. Participant enrolment and consent; 4. Sample collection; 5. Testing; and 6. Result disclosure and management. We recorded changes made over the study period to inform the post-implementation process map. Most changes occurred at stages: 1. Raising awareness, 4. Sample collection and 5. Testing. Lastly, a process map to inform the scale up of screening, was developed. Four key aspects of the gNBS process needing modification are: (1) growing awareness of screening amongst the public and HCPs; (2) building flexibility and accessibility into the consent process; (3) developing automation capabilities and infrastructure for large-scale sequencing and analysis, and (4) dedicated referral processes for infants who receive high-chance results. These findings demonstrate key system-level considerations and provide a foundation for implementing genomic newborn screening at scale within existing healthcare systems.
Short-read sequencing (SRS)-based disease-targeted NGS gene panels have revolutionized rare disease diagnostics but often leave autosomal recessive cases unsolved when only one pathogenic allele is detected. Missing variants may reside in deep intronic regions or involve structural variants (SVs) undetectable by SRS. To improve diagnostic yield, we implemented a cost-effective target capture-based long-read sequencing (LRS) assay covering 56 genes and retrospectively analyzed 78 patients suspected of autosomal recessive disorders who remained undiagnosed after SRS. Functional validation using reverse transcription PCR (RT-PCR) and minigene assays was performed to further determine pathogenicity. Target capture-based LRS solved 25.6% (20/78) of cases by identifying 10 SVs, 3 deep intronic variants experimentally confirmed to cause aberrant splicing, and 7 cases in which haplotype phasing confirmed that variants were in trans with the known pathogenic variant, leading to reclassification of the VUS as likely pathogenic. This study demonstrates that target capture-based LRS effectively detects diverse types of variants missed by SRS. Integrating this assay into stepwise diagnostic workflows offers a practical and cost-effective strategy to enhance diagnostic yield in autosomal recessive diseases. However, because this cohort was retrospectively defined based on a prior single-allele detection by SRS, this 25.6% (20/78) diagnostic yield reflects performance within a highly enriched population and should not be directly extrapolated to unselected rare disease cohorts.
Advances in DNA sequencing technology are increasing the rate of molecular diagnosis for patients and families with inherited Mendelian diseases. However, some patients remain unsolved following standard-of-care testing (typically either exome or genome sequencing), with structural variants (SVs) likely to account for a significant proportion of these missed diagnoses. We re-analysed ten research cases with the visual disorder foveal hypoplasia (FH) that were previously unsolved through whole exome sequencing (WES). We used SVRare, a tool that integrates outputs from Canvas and Manta and combines these with allele frequencies and information regarding their genomic context to highlight plausible pathogenic SVs. This analysis solved 2/10 cases. Expanding this strategy, we then used SVRare in a reverse genetics approach to analyse an FH-relevant gene panel in the 100,000 Genomes Project (100KGP) rare disease cohort. This identified potentially pathogenic SVs as the cause of disease in a further 11 previously unsolved cases with phenotypes overlapping FH. In total, 11 SVs in five genes were identified as the likely cause of FH in 13 patients: SLC38A8 (1 patient), PAX6 (3), OCA2 (3), GPR143 (5) and CACNA1F (1). This analysis also identified multiple carriers of an apparently novel deletion in OCA2. However, further analysis suggested that this is, in fact, the relatively common founder variant responsible for oculocutaneous albinism (OCA) in African populations, first identified over 30 years ago. These findings show that SVRare effectively identifies deleterious SVs and illustrates the challenges in reporting SVs, including the importance of accurate and consistent reporting of such variants.
The use of genomic sequencing in newborn screening is increasingly being piloted through research programmes worldwide. In parallel, an expanding body of attitudinal studies has examined stakeholder views as jurisdictions consider whether and how to implement genomic newborn screening (gNBS). To understand what perspectives have been represented thus far in stakeholder research and how those perspectives have been shaped by study design, we conducted a systemic mapping of 41 attitudinal studies about gNBS. Studies were conducted in eight countries, with more than half linked to ongoing pilot programmes. We observed a limited range of perspectives, with mothers and people with prior experience of a genetic condition in the family relatively frequently represented. As gNBS would primarily involve testing newborns who are not affected by genetic conditions, additional perspectives are needed. Studies varied considerably in how gNBS was described to participants. The issues most frequently explored concerned acceptability (n = 31), consent (n = 24), scope of screening (n = 26), psychosocial implications (n = 25), and data storage and secondary use (n = 22), whereas healthcare system readiness (n = 13) and equity considerations (n = 11) received comparatively less attention. Many studies left unaddressed participants' underlying assumptions about the predictive certainty of genomic findings, highlighting a need to situate gNBS within the realities of genomic uncertainty. At a time when policymakers are actively considering gNBS, this mapping highlights the need for careful interpretation of existing findings and identifies research priorities, particularly in relation to understanding gNBS as a public health programme.
Nonsyndromic cleft lip and palate (NSCLP) is a complex, multifactorial condition for which only about 25% of the genetic contribution has been identified. Although more than 60 genetic loci have been associated with NSCLP, a large portion of its heritability remains unexplained. Rare variants-often with stronger functional effects-are believed to account for some of this missing genetic risk. In this study, short-read whole-genome sequencing data from 786 NSCLP cases and 2149 controls were analyzed to identify genes enriched for rare protein-coding variants. Gene-based association testing, meta-analysis, functional prioritization, and effect-size estimation revealed several novel NSCLP candidate genes and confirmed associations with previously reported genes. The four novel candidate genes with the strongest association evidence were SCT, MALRD1, GPR156, and MYOCOS, all with p-values < 10⁻⁴. Replication of known genes was most robust for ARHGAP29, FGF8, SKI, and TP63. Pathway analyses showed significant enrichment of these genes in neuroactive ligand-receptor interactions, MAPK signaling, and other signal transduction pathways. Precise estimates of the risks conferred by the identified rare variants showed a substantial increase in NSCLP risk, with odds ratio point estimates between 2 and 4. These results provide strong support for a polygenic inheritance model in NSCLP, in which certain genes contribute varying levels of risk.
The combined newborn screening program for Spinal Muscular Atrophy (SMA) and Severe Combined Immunodeficiency (SCID) was evaluated in Liguria through a five-year pilot study involving 32,289 newborns. A single multiplex real-time PCR assay on dried blood spots enabled simultaneous detection of SMN1 exon 7 deletions and quantification of T-Cell Receptor Excision Circles (TREC) and Kappa-Deleting Recombination Excision Circles (KREC), achieving near-complete population coverage and a low recall rate. Ten newborns received a confirmed diagnosis of a targeted condition: five newborns were diagnosed with spinal muscular atrophy (SMA), of whom four were treated presymptomatically and achieved favorable clinical outcomes, whereas one with SMA type 0 died a few days after birth. Five newborns were diagnosed with immunodeficiencies, including two cases of adenosine deaminase (ADA)-related severe combined immunodeficiency (SCID), and three clinically significant secondary findings (idiopathic T-cell lymphopenia, DiGeorge syndrome, and transient B-cell lymphopenia). No false-negative cases were observed during follow-up. The TREC and KREC profiles were consistent with the underlying immunological diagnoses. Overall, the study demonstrates that combined SMA and SCID newborn screening is feasible, reliable, and clinically impactful, supporting its integration into public health screening programs.
Strømme syndrome (MIM 243605) or a form of syndromic microcephaly have both been reported to be caused by biallelic variants in CENPF. The common features associated with CENPF variants are microcephaly, jejunal atresia and eye abnormalities, but additional case reports have indicated more variable presentations. Here, we describe the diagnosis of an adult with Strømme syndrome and present a review of all 32 cases reported with genetic variants in CENPF, to highlight the common and diverse features. We find that neurological abnormalities, particularly microcephaly, are the most common feature (91% of individuals), with gastrointestinal (69%) and ocular features (44%) less common. While facial dysmorphism is widely reported, there are a broad variety of features noted, with no clear commonalities. The vast majority of genetic variants identified alter the reading frame through either nonsense, frameshift, or more rarely, essential splice site variants. Missense variants are seldomly reported; all are homozygous in affected individuals, but functional evidence has been presented for only one missense variant. Our summary illustrates the breadth of clinical features associated with Strømme syndrome caused by CENPF variants and the molecular genetics of CENPF reported thus far.
Rapid integration of genomics into clinical practice has increased the demand for genetic counselling services. While the genetic counsellor (GC) profession is well established in the Anglo-American healthcare systems, the D-A-CH countries, Germany, Austria, and Switzerland, operate under distinct, physician-led legal frameworks. To ensure high-quality care and professional mobility, a harmonised definition of the GC's role is necessary. The newly founded GfH Commission for GCs, in collaboration with the national human genetics societies of Germany (GfH), Austria (ÖGH), and Switzerland (SGMG), the Association of German Human Geneticists (BVDH), and the Swiss Association of GCs (ASCG), conducted a multi-stage consensus-building process. The methodology involved a comparative analysis of national legal prerequisites and the application of the entrustable professional activities framework to define the interprofessional interface between GCs and medical geneticists (MGs). The resulting scope of practice (SoP) categorizes competencies across three clinical phases: pre-counselling preparation, the active counselling process, and post-analytical follow-up. The SoP distinguishes between independent GC tasks, shared clinical responsibilities, and tasks requiring MGs. Key to this model is the preservation of the legal physician-prerogative for aspects like the final medical diagnosis and test-ordering while maximizing the GC’s contribution to patient-centred communication and care. This cross-border consensus represents a landmark in European professional policy, providing a scalable blueprint for the integration of GCs into regulated medical systems. By harmonising standards across the D-A-CH countries, the SoP ensures quality assurance, provides a robust evidence base for future legislative recognition and reimbursement of GCs, and facilitates professional mobility in Europe. Genetic counsellor, professional policy, D-A-CH region, interprofessional collaboration, entrustable professional activities, scope of practice, Genetische Fachberater, GfH, ÖGH, SGMG, BVDH, ASCG
PTEN hamartoma tumour syndrome (PHTS) is a diverse multi-system disorder predisposing to a high hereditary risk of breast, thyroid, endometrial, and a moderate risk of renal, and colorectal cancer and skin melanoma. Besides the risk of cancer, PHTS is also associated with benign tumours such as skin and connective tissue tumours, vascular malformations and neurodevelopmental disorders, including autism spectrum disorders. New evidence on cancer risks and the effectiveness of surveillance has been published since the last iteration of the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) guidelines from 2020, necessitating the update presented here A comprehensive literature review was undertaken, and guidelines were revised by clinicians with PHTS expertise from relevant medical disciplines, together with PHTS patients and their representatives. Revised recommendations were put forward for surveillance for breast, thyroid, endometrial, renal, and colorectal cancer and skin melanoma. The proposed cancer surveillance recommendations for PHTS require significant patient commitment as well as a coordinated multidisciplinary medical approach. There is a need for prospective evaluation of the effectiveness of these recommendations in the PHTS population.
