A renewed focus on disease prevention has placed genomics firmly in the spotlight. Policymakers and health services across Europe are considering ways to facilitate disease prevention and early disease detection through...A renewed focus on disease prevention has placed genomics firmly in the spotlight. Policymakers and health services across Europe are considering ways to facilitate disease prevention and early disease detection through population-level initiatives such as newborn genomic screening and polygenic risk scores. This commentary explores, through the lens of duty-based ethics, the ethical considerations in the design of genomic screening programmes. As genomic medicine becomes embedded in public health strategies, a robust ethical framework is essential to ensure that its promises are realised equitably and responsibly.
Despite considerable efforts investigating the genetic aetiology of rare diseases in the past decades, approximately 50% of cases remain without a genetic diagnosis. Many missing diagnoses can be attributed to the limita...Despite considerable efforts investigating the genetic aetiology of rare diseases in the past decades, approximately 50% of cases remain without a genetic diagnosis. Many missing diagnoses can be attributed to the limitations of short-read sequencing (SRS), compounded by (mis)-alignment to incomplete and inaccurate reference genomes such as GRCh37/38. SRS cannot resolve many regions that are challenging to map, including large contiguous tandem repeats, segmental duplications (SDs), sites of complex structural variants (SV), or highly diverged population-specific loci. Long-read sequencing (LRS) technologies have delivered the first complete human genome assembly, T2T-CHM13. Compared to GRCh38, T2T-CHM13 resolves the remaining 8% of the genome, corrects structural errors and improves both SRS- and LRS-based read mapping and variant discovery. LRS has also facilitated the generation of high-quality, haplotype-resolved assemblies from globally diverse cohorts, enabling the construction of pangenome references for multiple ancestral groups. By representing more human genomic variation, a pangenome reference can improve mapping and variant calling accuracy. These new genome resources represent alternative reference paradigms that have the potential to uncover pathogenic variants underlying unsolved rare genetic diseases. Here, we examine the limitations of GRCh38 for rare disease variant discovery and explore how emerging resources like T2T-CHM13 and pangenomes can improve accuracy. We highlight key studies that have leveraged these references to improve diagnostic outcomes and discuss the potential for broader adoption. Finally, we consider the current barriers to research and clinical implementation and outline available resources and tools to expedite the transition to these new reference models.
Floris M, Moschella A, Capasso M
… +6 more, Alcalay M, Iascone MR, Grammatico P, Gasparini P, Miozzo MR, Italian Society of Human Genetics (SIGU) Working Group on Pharmacogenomics
Peutz-Jeghers syndrome (PJS) is a very rare autosomal dominant disorder associated with an increased risk of gastrointestinal and gynecological cancers. However, risk estimates vary widely, due to the small size and retr...Peutz-Jeghers syndrome (PJS) is a very rare autosomal dominant disorder associated with an increased risk of gastrointestinal and gynecological cancers. However, risk estimates vary widely, due to the small size and retrospective nature of most studies, which may introduce recruitment bias. Accurate data are needed to improve cancer screening. The aim of this study was to estimate cancer risks in a large cohort of PJS patients. A total of 161 patients were included, half of whom were prospectively monitored as part of a surveillance network. This makes it one of the largest cohorts of PJS patients to date. We estimated age-dependent cancer risks using the Genotype Restricted Likelihood (GRL) method to correct for ascertainment bias. Standardized mortality ratios (SMRs) were calculated to assess mortality. PJS patients showed an increased risk of cancer, particularly early-onset cancers (cumulative risk before age 70: 18.1% in men, 36.8% in women). This resulted in excess mortality, especially among young women. The most frequent cancers were breast, lung, and cervical cancers. Small bowel was the site with the highest relative risk. Although the risk of pancreatic adenocarcinoma (PDAC) was elevated, it was much lower than had been reported previously (relative risk at age 50: 11.8). Degenerated intraductal papillary mucinous neoplasms (IPMN) may contribute to the risk of PDAC in PJS, while this carcinogenesis pathway accounts for only 10% of PDACs overall. We report an unexpectedly high risk of lung adenocarcinoma, calling into question the relevance of lung cancer screening in PJS.
Here, we present EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders. They aim is to aid clinical genetic laboratories in testing, and unequivocal and comprehensive reporting of RYR1...Here, we present EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders. They aim is to aid clinical genetic laboratories in testing, and unequivocal and comprehensive reporting of RYR1 variants for the benefit of patients and their relatives. These guidelines are supported by experts in the field of anaesthesia, (paediatric) neurology, clinical genetics and clinical laboratory genetics. The ryanodine receptor type 1 is a large calcium channel that regulates calcium release from the sarcoplasmic reticulum resulting in muscle contraction. This receptor is encoded by the RYR1 gene and expressed predominantly in skeletal muscle. Pathogenic RYR1 variants are associated with several allelic disorders: malignant hyperthermia, a hypermetabolic reaction to certain anaesthetics in otherwise healthy individuals, exertional rhabdomyolysis and both autosomal dominant and recessive congenital myopathies. In general, RYR1 gain-of-function variants are associated with malignant hyperthermia susceptibility, whereas dominant-negative and loss-of-function variants are associated with dominant and recessive myopathies, respectively. However, a small subset of RYR1 variants is associated with a combination of dominant malignant hyperthermia susceptibility with either a dominant or a recessive myopathy or exertional rhabdomyolysis. The apparent discrepancy between molecular mechanisms and different phenotypes is currently poorly understood. As a consequence, the context-dependent interpretation of RYR1 variants is challenging in diagnostic genetic testing. In particular, it is not trivial to assign a possible associated risk for an allelic disorder for an individual or their relatives, which is especially relevant in family planning.
Osteogenesis imperfecta (OI) is under consideration for inclusion in several genomic newborn screening initiatives, but its penetrance in clinically-unselected populations is currently unknown. It is an exemplar conditio...Osteogenesis imperfecta (OI) is under consideration for inclusion in several genomic newborn screening initiatives, but its penetrance in clinically-unselected populations is currently unknown. It is an exemplar condition for evaluating penetrance in adult cohorts due to its relatively low mortality, variable expressivity and link to several large genes. Using genome sequencing data from ~500,000 adults in UK Biobank, we curated a set of rare pathogenic/likely pathogenic (P/LP) variants in COL1A1, COL1A2 and IFITM5 using annotations from gnomAD, ClinVar and SpliceAI. Analysis of summed read-count data from genome and exome sequencing led to exclusion of 16 mosaic variants with consistently low allelic balance of 3.4-35.9%. We identified 61 likely constitutive heterozygous P/LP variants in COL1A1 and COL1A2 (29 loss-of-function or splice variants and 32 missense) in 115 participants, with a mean age at recruitment of 55.1 years; no P/LP variants were identified in IFITM5. Phenotypes were assessed using ICD-10 codes, self-reports and heel bone mineral density (BMD). Overall disease penetrance was lower than anticipated: 40.7% for COL1A1 and 21.3% for COL1A2, potentially due to depletion of severe early-onset disease. When considering only truncating variants in COL1A1, disease penetrance increased to 73.1%, and 90% of individuals had reduced levels of circulating COL1A1 protein. For COL1A2, BMD data supported the low penetrance, whereas for COL1A1, data suggested the possibility of a subclinical phenotype. Overall, for P/LP missense variants (including those altering Gly-Xaa-Yaa repeats), the low penetrance observed suggests reliance on current ClinVar assertions to support pathogenicity may overstate OI risk in population screening.
Host-pathogen interactions are shaped by the nature of the pathogen and by host-related factors. Human host responses can be characterized in microbe-stimulated immune cells using transcriptomics. We set out to character...Host-pathogen interactions are shaped by the nature of the pathogen and by host-related factors. Human host responses can be characterized in microbe-stimulated immune cells using transcriptomics. We set out to characterize gene expression changes as a result of microbial in vitro stimulation in medium-cultured human primary immune cells, using four pathogen ligands representing bacteria (LPS and S. aureus), viruses (Poly(I:C)) and fungi (C. albicans) for 4 and 24 h, resulting in a total of 52 samples for analysis. We analyze the transcriptional changes on gene and pathway levels, highlighting common and distinct effects of pathogen stimulation. We highlight genes without a known function that were differentially expressed as a common effect of pathogen stimulation. Amongst those, we find uncharacterized genes such as KIAA0040 and CYRIA to be co-expressed with genes involved in innate immunity and downstream signaling from the PRRs, respectively. Further linking our differential expression data to IEI, we identify 901 variants in uncharacterized genes in a cohort of patients with rare immune disorders, prioritizing 5 candidate variants in 4 genes that could underlie these diseases. Our results therefore indicate a potential role of these genes in the human immune response and provide further candidate variants for rare immune-mediated diseases.
RAC1 is a signal transducer essential for neurodevelopment. Missense variants in RAC1 cause heterogeneous neurodevelopmental disorders whose features include intellectual disability and developmental delay. Individuals w...RAC1 is a signal transducer essential for neurodevelopment. Missense variants in RAC1 cause heterogeneous neurodevelopmental disorders whose features include intellectual disability and developmental delay. Individuals with RAC1 variants are categorized by head circumference into microcephalic, normocephalic and macrocephalic groups. We previously described a cohort of individuals with variants affecting the N-terminal part (Q61-R68) of switch II, a functional domain of RAC1. This cohort was normocephalic and their variants increased RAC1 signalling activity. Here, we report 15 new individuals with variants in switch II of RAC1. We describe clinical features for two individuals with variants affecting the N-terminal part of switch II (Q61-R68) and four individuals with variants in its C-terminal part (P69-Q74). All individuals exhibit intellectual disabilities and neuroradiological anomalies. Consistent with our previous study, individuals with variants in the N-terminal part of switch II were normocephalic. By contrast, individuals with variants in the C-terminal part of switch II exhibited microcephaly. Cell-based assays revealed that N- and C-terminal variants affect RAC1 function differently: N-terminal variants are activating, while C-terminal variants are dominant-negative. In a Drosophila model, we observe divergent effects on neuronal morphology, with switch II N-terminal variants increasing the complexity of dendritic arbors, while switch II C-terminal variants reduce dendritic complexity. Switch II N-terminal variants increase locomotor activity of adult Drosophila, while C-terminal variants had minimal effect, suggesting diverging effects on neuronal function and behaviour. We conclude that variants affecting N- and C-terminal parts of RAC1 switch II cause phenotypically and mechanistically distinct disorders.
Brown GL, Walker L, Afolabi MA
… +16 more, Bain PA, Bonilha A, Chaudhari BP, Christodoulou J, Dai Z, Friedman JM, Gaviglio A, Green RC, Jagu S, Knoppers BM, Newson AJ, Stark Z, Vears DF, Wilson A, Bombard Y, Lewis ACF
The integration of genomic sequencing into newborn screening (genomic newborn screening; gNBS) has the potential to identify more presymptomatic babies who could benefit from early intervention compared to traditional un...The integration of genomic sequencing into newborn screening (genomic newborn screening; gNBS) has the potential to identify more presymptomatic babies who could benefit from early intervention compared to traditional universal newborn screening (NBS). Realizing these benefits requires careful navigation of ethical, legal, and social implications (ELSI) to minimize harms, promote equity, and maintain trust in NBS programs. The primary objective of this scoping review is to synthesize the ELSI discussed in the gNBS literature, to support implementation and identify knowledge gaps. A secondary objective is to characterize the landscape and contours of the gNBS field. This review, conducted in July 2025, includes academic literature addressing genomic sequencing as a first‑line NBS screen. ELSI were identified within each publication, and these informed the development of a set of decision points with ELSI dimensions within gNBS. A total of 485 publications met inclusion criteria, with the first published in 1987. The volume of publications increased over time, with growing proportions of empirical studies and work associated with gNBS projects, alongside a decreasing proportion of publications from North America. In total, 3781 ELSI considerations were charted using AI-assisted methods, relevant to 59 decision points organized into nine areas. Current scholarship is concentrated on early implementation questions, while long‑term operational needs-such as data stewardship, clinical follow‑up, and sustainable governance-remain underexplored. These gaps, together with limited contributions from many regions due to a multitude of factors, highlight the need for more diverse, empirically grounded, and forward‑looking research to support responsible decisions around gNBS.
Reproductive genetic carrier screening (RGCS) raises the question of which conditions should be included. Severity has long been the guiding criterion: conditions causing serious suffering, justify offering reproductive...Reproductive genetic carrier screening (RGCS) raises the question of which conditions should be included. Severity has long been the guiding criterion: conditions causing serious suffering, justify offering reproductive options. Some propose replacing severity with utility, defined as the usefulness of information for reproductive decision-making. Proponents of this approach claim that utility aligns more directly with RGCS's aim of supporting informed choice while avoiding stigmatizing judgments about genetic conditions. This article challenges that proposal. First, utility depends on severity: contextual factors such as preimplantation genetic testing become relevant only once a condition is judged sufficiently severe. Second, while severity retains some clinical anchors such as prognosis, functional limitations, treatment burden, utility dissolves into subjective preferences, making it ill-suited for guiding population-level policy. Third, collective recognition of severity provides prospective parents with a moral frame of reference that eases the heavy responsibility of reproductive decisions. Fourth, avoiding severity judgments in the name of respect risks both invalidating the suffering of affected individuals and bypassing the democratic deliberation essential to public healthcare policy. We argue that value judgments in RGCS are inevitable and necessary. Severity, though imperfect, provides the shared normative anchor needed for publicly funded programs. Facing suffering honestly, acknowledging severity while respecting those who live with severe conditions, is the foundation of a compassionate and democratic RGCS policy.
The integration of genomic sequencing into public health newborn screening (NBS), gNBS, could identify far more children that would meet screening guidelines than existing biochemical NBS. The retention of genomic data f...The integration of genomic sequencing into public health newborn screening (NBS), gNBS, could identify far more children that would meet screening guidelines than existing biochemical NBS. The retention of genomic data from gNBS could have huge benefits for research and could also enable potential clinical reuse. Many different ethical frameworks can support not seeking parental permission for traditional NBS, and indeed, most programs around the world do not do so, and are either mandatory or allow for an opt-out. Many NBS programs retain the underlying sample for anonymized or pseudonymized/coded research. This is proving to be a controversial aspect of NBS. While the appropriate consent regime(s) for the screening aims for gNBS remain unclear, we put forward arguments for the appropriate consent regimes for the retention and use of genomic data in gNBS. We review the different ethical frameworks that justify screening on the one hand, and further storage and uses of the data on the other. We argue that parental permission via an informed choice should be sought for genomic data retention for research purposes, that individual genomic data may be retained by the program for QA/QI purposes (but only for long enough to permit these purposes), and that no parental permission is needed to update aggregated genomic databases (e.g., allele frequencies). For clinical recontact, the appropriate consent regime for retaining genomic data will depend on the jurisdiction, but parents should be very thoroughly educated on the prospect of re-contact if this is planned.
Genetics in medicine is rapidly becoming integral to European healthcare, yet access to high-quality genetic counseling remains inconsistent. Genetic counseling empowers patients to make informed decisions about genetic...Genetics in medicine is rapidly becoming integral to European healthcare, yet access to high-quality genetic counseling remains inconsistent. Genetic counseling empowers patients to make informed decisions about genetic testing, improves clinical management, and mitigates psychosocial harm. Despite growing demand, the genetic counselor profession lacks legal recognition, standardized education, and harmonized regulation across European Union (EU) Member States. Current fragmentation, which is evident in separate national laws and variable practices, poses systemic risks, including inequitable care and credentialing barriers. This paper argues that harmonization is essential to ensure ethical, safe, and effective genetic services. We recommend EU-wide legal recognition of genetic counselors, standardized education through EBMG-accredited programs, and investment in workforce development and education. Coordinated action can safeguard individuals' rights, support professional mobility, and enable responsible integration of genomics into healthcare.
Eur J Hum Genet
· 2026 Jun · PMID 42082645
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The classification of congenital malformations has been transformed over recent decades by advances in genetic analysis, so that the natural history of many disorders during childhood is well described. However, implicat...The classification of congenital malformations has been transformed over recent decades by advances in genetic analysis, so that the natural history of many disorders during childhood is well described. However, implications for adult prognosis and survival are often poorly documented. In Apert syndrome, caused by heterozygous germline mutations in the fibroblast growth factor receptor type 2 gene (FGFR2), the question of prognosis is particularly pertinent because FGFR2 is a known cancer driver gene (oncogene) and the identical mutations, when arising somatically, are enriched in specific tumours, notably endometrial carcinoma. We exploited a unique resource provided by a series of 24 UK patients described by Dr Eric Blank in 1960, and used tracing of cancer events and deaths through the National Health Service Central Register to determine the long-term outcome of these individuals until 2013, a period spanning 53 years. Twelve individuals (50%) were still alive and without any cancer registration, at the end of the study; of the remainder, two could not be traced and ten were known to have died, with four deaths related to malignancies. We conclude that Apert syndrome is not, in many affected individuals, associated either with substantial shortening of lifespan, or with a high risk of developing particular types of cancer. Explanation of the lack of strong cancer predisposition, despite the oncogenic nature of the FGFR2 mutations, may lie in the different signalling relationship that a mutant cell has with its neighbours when the mutation is present constitutionally, compared to occurrence as a somatic change.
This cross-sectional online survey study explores the landscape of medical training on genetic therapies, assessing the experience, expectations and attitudes of medical geneticists, other specialists, and medical traine...This cross-sectional online survey study explores the landscape of medical training on genetic therapies, assessing the experience, expectations and attitudes of medical geneticists, other specialists, and medical trainees in Canada and USA. Among the 315 participants, only 17% reported being "very familiar" with genetic therapies, and 70% expressed dissatisfaction with current training in this area. Across all groups, there was a consistently low level of satisfaction with existing training on genetic therapies, coupled with a strong consensus that this topic should be better integrated into medical programs. Physicians with specialization in genetics reported the highest familiarity and the most experience in teaching about genetic therapies, covering a broader range of topics than other specialties. All specialties acknowledged the pivotal role of medical geneticists in advancing education on genetic therapies. Instead of each specialty designing their own fellowship programs independently, there was a clear preference to do so in collaboration with medical geneticists. Furthermore, most respondents advocated for the introduction of genetic therapy education earlier in medical training, during medical school and residency programs. Our study highlights a clear and pressing need for comprehensive, stage-specific education reform about genetic therapies. Medical geneticists are uniquely positioned to lead and support these educational efforts, ensuring the successful adoption of advanced genetic therapies in patient care.
Lucas-Castro E, Ramos-Mejía R, Sánchez-Gaya V
… +4 more, Rada-Iglesias Á, Caíno S, Fano V, Heath KE
Eur J Hum Genet
· 2026 Jun · PMID 42069959
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Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case, a 9 ye...Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case, a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients. No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3. As hypothesized for deletions detected in this disorder we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression. Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder.