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
The Italian Society of Human Genetics (SIGU) Working Group on Pharmacogenomics has released recommendations for the implementation, interpretation and reporting of germline pharmacogenetic testing in clinical practice wi...The Italian Society of Human Genetics (SIGU) Working Group on Pharmacogenomics has released recommendations for the implementation, interpretation and reporting of germline pharmacogenetic testing in clinical practice within the Italian National Health Service (SSN). These guidelines outline the key principles for the responsible use, reporting, and interpretation of pharmacogenetic data, emphasizing clinical validity, clinical utility, cost-effectiveness, and ethical considerations. With the aim of promoting a systematic standardized, and evidence-based implementation of germline pharmacogenetic testing in Italy, SIGU strongly recommends addressing the following points: (1) Pharmacogenetic testing should be performed based on validated scientific evidence, primarily following Association for Molecular Pathology (AMP) and Dutch Pharmacogenetics Working Group (DPWG) guidelines, and restricted to gene-drug pairs with ClinPGx clinical annotation level 1 A. (2) Patients must be appropriately informed and provide specific consent, particularly when pharmacogenetic data are derived as secondary findings from diagnostic next generation sequencing (NGS) analyses. (3) Testing should prioritize clinically actionable variants that influence therapeutic efficacy or prevent severe adverse drug reactions. (4) The interpretation and reporting of results must be carried out by a qualified geneticist in collaboration with clinical pharmacologists to ensure appropriate therapeutic recommendations. (5) The implementation of pharmacogenetic testing should be supported by robust quality assurance procedures in laboratories, in line with international standards. (6) The inclusion of pharmacogenetic tests in the Italian LEA (Essential Levels of Assistance) should be updated in accordance with international evidence and EMA-AIFA recommendations. (7) Further pharmaco-economic and psychosocial research is needed to evaluate the impact of pre-emptive versus reactive testing strategies on patient outcomes and healthcare sustainability.
Rare tumours are variously defined but usually affect not more than 1 in 100000 people. They can be present at birth, in childhood or later in life. The diagnosis of a rare tumour can sometimes point to an underlying her...Rare tumours are variously defined but usually affect not more than 1 in 100000 people. They can be present at birth, in childhood or later in life. The diagnosis of a rare tumour can sometimes point to an underlying hereditary condition, and one should take into account important considerations that can increase suspicion of a genetic cause of the disease. While some rare neoplasms are highly specific of a hereditary tumour susceptibility syndrome (and can be almost pathognomonic), thus prompting a direct genetic evaluation, most rare neoplasms may appear within the context of multi-tumour susceptibility syndromes, and here they add important weight to the global assessment when considering a genetic referral. Despite their low frequency, novel associations between rare neoplasms and hereditary conditions continue to emerge, although a solid association is often lacking. On the contrary, some infrequent tumours are nearly always non-hereditary (sporadic) in nature. Of note, the definition of rare tumours should be age-adjusted as paediatric tumours are by definition rare when compared with adult tumours in absolute terms. Therefore, in this review, in the paediatric section, we focus on tumours that occur rarely in childhood. This can include cancers that typically occur in adults, but in this case, it appears in a child. Both situations are a strong indication for genetic testing. In this review, we described different scenarios in which rare neoplasms can serve as indications (or not) for an underlying inherited cancer susceptibility.
Eur J Hum Genet
· 2026 Jun · PMID 41917265
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As part of the Danish National Genome Centre (DNGC) initiative, the Central Denmark Region has implemented short-read whole-genome sequencing (srWGS) as a first-tier diagnostic tool for suspected monogenetic disorders. D...As part of the Danish National Genome Centre (DNGC) initiative, the Central Denmark Region has implemented short-read whole-genome sequencing (srWGS) as a first-tier diagnostic tool for suspected monogenetic disorders. Despite increasing adoption of genome sequencing, evidence from large-scale implementation across clinical specialties remains limited. Here, we evaluate the implementation from patient inclusion and srWGS scaling to diagnostic performance. From 2021 to 2024, we sequenced 2317 patients with suspected genetic diseases across a wide range of medical specialities. Following clinical evaluation and informed consent, Illumina srWGS was performed. Patients were categorised into clinical subgroups based on phenotype and age to support targeted variant filtration and germline variant reporting. The primary outcome was diagnostic yield across all disease groups/categories. The project is a public/private partnership co-funded by the Novo Nordisk Foundation. Diagnostic yield ranged from 6% in children with cancerto 60% in patients with skin disorders, with an overall yield of 20%. We observed substantial variation in the clinical use of srWGS as a first-tier diagnostic tool across patient categories. Regional implementation of srWGS within the DNGC framework demonstrates its scalability as a first-tier diagnostic tool for monogenic disorders. Importantly, the combination of expert-guided inclusion criteria for srWGS and mixed public/private funding has ensured equitable access to genetic diagnostics. We identify patient groups with high diagnostic returns well suited for srWGS, as well as groups where alternative strategies could also be applied.
van Zanten ES, Loehrer EA, van Meurs JBJ
… +4 more, Narcisi R, Gribnau JH, Poot RA, Adams HHH
Eur J Hum Genet
· 2026 Jun · PMID 41917264
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Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally,...Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool in biomedical research, enabling the study of cellular function and early disease mechanisms within patient-specific genetic contexts. Traditionally, iPSCs have been used to model monogenic diseases, where highly penetrant variants produce robust cellular phenotypes detectable in few cell lines. Recent advances in scalability and standardisation now enable systematic comparisons across many donors. This development is particularly relevant for complex diseases, which are driven by numerous genetic variants with small individual effects and therefore require population-scale designs to resolve genotype-phenotype relationships. However, several limitations of iPSC technology continue to challenge the reliability and reproducibility of such studies, constraining their translational relevance. Here, we review the challenges and opportunities of using iPSCs to model complex diseases, structured around three key themes: detecting subtle effects, modelling environmental context, and expanding genetic diversity.
Mitchell LA, Schmidt J, Souzeau E
… +11 more, Knight LSW, Maxwell G, Dubowsky A, Lim R, Formaini E, Welland M, Simons C, MacArthur DG, Wiggs JL, Craig JE, Siggs OM
Eur J Hum Genet
· 2026 May · PMID 41888561
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Axenfeld-Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the PITX2 or FOXC1 loci, yet many cases still remain undiagn...Axenfeld-Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the PITX2 or FOXC1 loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two families with non-coding structural variants associated with a typical presentation of PITX2-associated ARS: one family with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2, and the second family with a 12.54 Mb inversion displacing the PITX2 gene from these same enhancer elements. Neither variant disrupted the PITX2 gene itself, and therefore both were expected to reduce PITX2 expression by disrupting its proximity or access to enhancer elements. PITX2 enhancer-disrupting inversions are an emerging genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.
Miranda-Alcaraz L, Mora-Gómez M, Gallego-Zazo N
… +18 more, Cruz-Utrilla A, Del Cerro Marín MJ, Ochoa Parra N, Martín de Miguel I, Gutiérrez Ortiz E, Jiménez-Estrada JA, Parra A, Cazalla M, Ramos S, Rodríguez-Canó M, Silván C, Vásquez-Amell V, Arias P, Nevado J, de Jesús Pérez V, Lapunzina P, Escribano-Subías P, Tenorio-Castano J
Eur J Hum Genet
· 2026 Jun · PMID 41882294
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Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary artery pressure, leading to heart failure and premature death if untreated. Genetic factors significantly contribute to PAH, a...Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary artery pressure, leading to heart failure and premature death if untreated. Genetic factors significantly contribute to PAH, and several genes have been linked to its development. According to the ClinGen PH-GCEP group, 12 genes have definitive evidence of association with PAH, three have moderate evidence, six have limited evidence, and five remain disputed due to insufficient genetic data. The aim of this study was to analyze variants in genes without definitive evidence in a cohort of 1480 individuals (954 PAH patients and 526 relatives) by next-generation sequencing (NGS). Variants were prioritized through a custom pipeline developed in-house and classification was performed according to ACMG guidelines. A total of 32 different variants were identified in 42 individuals (32 patients and 10 relatives, five of whom developed the disease): Two pathogenic or likely pathogenic variants in ABCC8 and 30 variants of unknown significance (VUS) in 10 genes (ABCC8, AQP1, BMPR1A, BMPR1B, BMP10, FBLN2, NOTCH3, SMAD1, SMAD4 and TET2). On the opposite, no candidate variants were detected in GGCX, KLF2, KLK1 or PDGFD genes. These findings provide further genetic evidence supporting the association of ABCC8 and related genes with PAH, while no candidate variants were detected in GGCX, KLF2, KLK1, or PDGFD. Further research is needed to confirm the functional impact of these variants.
Sabbagh Q, Cenni C, Haghshenas S
… +57 more, Alessandri JL, Bak M, Bayat A, Barat-Houari M, Brusco A, Busa T, Calaya A, Calvert P, Cormier-Daire V, Coubes C, Duffourd Y, Ferrero GB, Guimier A, Haye D, Hjortshøj TD, Lambert L, Larsen KB, Lauzon-Young C, Lesca G, Chatron N, Levy MA, Lopergolo D, Margot H, McConkey H, Monin P, Morel G, Naudion S, Nizon M, Odent S, Pinson L, Pons L, Putoux A, Rio M, Rossi M, Rouaux L, Rouxel F, Ruiz-Pallares N, Sanchez E, Pagano S, Santorelli FM, Sauvestre C, Schymick JC, Siu VM, Spodenkiewicz M, Tedder M, Tharreau M, Mau-Them FT, Tümer Z, Valenzuela I, Van Gils J, Willems M, Kirchhoff A, Krawitz P, Kerkhof J, Schuurs-Hoeijmakers JHM, Sadikovic B, Geneviève D
Eur J Hum Genet
· 2026 Jun · PMID 41882293
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PACS1-related disorder (PACS1-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C > T p.(Arg203Trp) gain-of-func...PACS1-related disorder (PACS1-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C > T p.(Arg203Trp) gain-of-function variant. Although core clinical features have been delineated, systematic data on developmental milestones, growth parameters, and clinical variability remain limited. We assembled a series of 24 previously unreported, unrelated individuals with PACS1-RD and compared their clinical and molecular features with 84 individuals from the literature. Genome-wide DNA methylation profiling was performed on peripheral blood DNA using bisulfite sequencing, interrogating ~860,000 CpG sites. Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%). Compared with the literature, our series showed a higher prevalence of cryptorchidism (77.8%), congenital heart defect (45.8%), and hypotonia (75%). Methylation analysis identified a specific episignature for PACS1-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant. This episignature further enabled PACS1-RD diagnosis in one unsolved individual initially suspected of Kabuki syndrome. These findings refine the clinical delineation of PACS1-RD and establish an episignature that will support diagnosis in unresolved neurodevelopmental disorders and guide pathogenicity assessment of non-recurrent PACS1 variants.
Haemochromatosis is a genetic disorder of iron homeostasis. It can be caused by mutations in genes encoding the iron-regulatory hormone hepcidin (HAMP), and/or genes that regulate hepcidin expression (HFE, HJV, TFR2), or...Haemochromatosis is a genetic disorder of iron homeostasis. It can be caused by mutations in genes encoding the iron-regulatory hormone hepcidin (HAMP), and/or genes that regulate hepcidin expression (HFE, HJV, TFR2), or a gain-of-function mutation in the gene encoding hepcidin receptor ferroportin (FPN1/SLC40A1). HFE-related haemochromatosis is prevalent predominantly in individuals of northern European descent. These mutations result in dysregulated levels or activity of hepcidin, leading to high iron-saturation of transferrin followed by progressive liver iron accumulation in the absence of anaemia. To enable and enhance the understanding of haemochromatosis in both researchers and prospective medics, this review collates and discusses the genetic basis and consequent pathophysiology of the different types of haemochromatosis within a single, comparative review. The discussion is supported by figures and a summary table that compares the haemochromatosis types for prevalence, clinical manifestations, primary organs affected, iron-related biochemical parameters and mechanisms of iron loading. Also, gain-of-function ferroportin mutation is compared to ferroportin disease, which is a loss-of-function ferroportin mutation, and shows a tendency to anaemia. Essentially, HFE-related haemochromatosis (common type) and TFR2-related haemochromatosis (rare type) show late-onset, milder and gradual iron loading, and often involve liver and joint damage. In contrast, HJV- and HAMP-related haemochromatosis (rare types) show severe and rapid iron loading in the first three decades of life, with notable cardiac and endocrine complications. Hepcidin levels are more markedly decreased in HJV-related haemochromatosis compared to HFE and TFR2 types. There are minimal to absent levels of hepcidin in HAMP-related haemochromatosis.
Eur J Hum Genet
· 2026 May · PMID 41851263
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"Alport spectrum disorder" describes a phenotypically and genotypically multifaceted disease entity encompassing classic autosomal recessive and X-linked Alport syndrome (AS) but also more heterogenous and typically mild..."Alport spectrum disorder" describes a phenotypically and genotypically multifaceted disease entity encompassing classic autosomal recessive and X-linked Alport syndrome (AS) but also more heterogenous and typically milder, yet not benign, hematuric phenotypes like autosomal dominant AS, formerly also known as thin basement membrane nephropathy (TBMN). Alport spectrum disorder is associated with disease-causing variants in the type IV collagen genes COL4A3, COL4A4 and COL4A5. Variants and genotypes, reported by a genetic diagnostics lab between 2009 and 2014, of 91 index cases with the clinical tentative diagnosis of AS (66/91), TBMN (21/91), or AS/TBMN (not specified further; 4/91), were reassessed based on 2015 ACMG (American College of Medical Genetics and Genomics) criteria and current amendments. 80 different variants, all originally reported as "mutations", and their genotypes have been reassessed (COL4A3: 21/80, COL4A4: 15/80, COL4A5: 44/80). In 10/80 variants, classification changed from disease-causing to variant of uncertain significance (VUS). 69/91 (76%) index cases included in the analysis could be classified as solved. 22/91 (24%) index cases had an ambiguous result either on variant, genotype, or both variant and genotype level. VUS cases had a significantly more limited phenotype (e.g., isolated microscopic hematuria) compared to non-downgraded cases (e.g., additional extrarenal manifestations). Reassessment of variants/genotypes in this study showed a significant reduction in unequivocal genetic diagnoses highlighting variant and genotype interpretation as a dynamic process. Genetic reports of individuals with suspected Alport spectrum disorder, especially those obtained in the pre-ACMG criteria era, should therefore be critically evaluated.
Over the past three decades, Hereditary Cancer Testing (HCT) has evolved from single gene assays into multigene panel testing (MGPT), which allows for the screening of all known hereditary cancer genes in a single assay....Over the past three decades, Hereditary Cancer Testing (HCT) has evolved from single gene assays into multigene panel testing (MGPT), which allows for the screening of all known hereditary cancer genes in a single assay. MGPT is currently the standard approach for clinical HCT. However, with decreasing sequencing costs and increased instrument throughput, the scalability of exome sequencing (ES) and genome sequencing (GS) for HCT indications is becoming more viable. These methods provide broader insights into the coding exons and/or the entire genome, respectively. ES/GS data can also be reanalyzed to identify variants in novel genes that were not characterized at the time of initial testing, or to support research efforts aimed at uncovering additional associations between germline variants and cancer predisposition. Additionally, the emerging use of long-read sequencing (LRS) is noteworthy, enabling improved variant detection compared to short-read sequencing, especially for complex/structural variants and variation in difficult-to-sequence or paralogous regions in genes such as PMS2. This has the potential to increase the accuracy of HCT, reduce the turnaround time, find previously unidentifiable cancer risk variants, and ultimately increase the diagnostic yield. This article provides a comprehensive summary of the sequencing approaches used in HCT, discussing their strengths and limitations. We also highlight the added value of complementing DNA-only testing with RNA and tumor sequencing. Furthermore, we explore LRS-based approaches and discuss opportunities for their implementation in routine genetic testing for hereditary cancer.
Zeuzem N, Quilan M, Dominguez-Valentin M
… +23 more, Baert-Desurmont S, Horlacher M, Della Valle A, Esperon P, Neffa F, Bonfim Machado-Lopes TM, de Oliveira Nascimento IL, Pereira Toralles MB, Bomfim-Palma TF, Pavicic WH, Vaccaro CA, Spirandelli F, Santamaria-Quesada C, Jimenez G, Vaca-Paniagua F, Perdomo S, López Rivera JJ, Torrezan GT, Carraro DM, Brieger A, Serve H, Martins A, Plotz G
Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Ly...Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.
Leshchynska I, Das D, O'Reilly V
… +15 more, Sipka A, Iyer K, Alankarage D, Rath E, Kumar A, Kurt BA, Voydanoff ME, Congenital Heart Disease Synergy Study group, Stevenson RE, Winlaw DS, Ascher DB, Giannoulatou E, Mark PR, Dunwoodie SL, Chapman G
Eur J Hum Genet
· 2026 May · PMID 41851260
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The spectrum of congenital malformations in VACTERL association varies among patients and can be differentially diagnosed with CHARGE syndrome, Fanconi anaemia, and others (reviewed in Solomon 2011). Despite overlapping...The spectrum of congenital malformations in VACTERL association varies among patients and can be differentially diagnosed with CHARGE syndrome, Fanconi anaemia, and others (reviewed in Solomon 2011). Despite overlapping clinical findings, the genetic causes of these diseases are distinct. In this context, unbiased whole genome sequencing can assist in differential diagnoses, as well as identify new gene-disease associations. In this report, we demonstrate that whole genome sequencing of a proband with suspected VACTERL association revealed two gene variants in the ribosomal genes RPL18 (NM_000979.4 c.397 G > C p.(Gly133Arg)) and RPS6 (NM_001010.3: c.370 C > G p.(Leu124Val)). Mutations in ribosomal genes are associated with Diamond-Blackfan anaemia, a condition that shares phenotypic similarities with Fanconi anaemia. Our modelling and functional assessment of the identified variants strongly indicate pathogenicity of the RPL18:p.(G133R) variant as it is novel, displays reduced expression and stability and abnormal intracellular distribution, and interferes with protein synthesis in cultured cells. The RPS6:p.(L124V) variant reduced protein expression and altered cytoplasmic distribution but does not interfere with protein synthesis in cultured cells. Overall, our study indicates the significant advantage of using unbiased whole genome sequencing for the examination of patients with complex congenital malformations.
Kramers RN, van der Schoot V, Brilstra EH
… +6 more, Cohen de Lara M, Giesbertz NAA, Kerstjens-Frederikse MS, Oosterwijk C, Verweij JJT, Bunnik EM
Eur J Hum Genet
· 2026 May · PMID 41851259
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Preimplantation genetic testing (PGT) as a reproductive technology to prevent the transmission of genetic anomalies to offspring has been available for decades. In the Netherlands, a National Indications Committee was ta...Preimplantation genetic testing (PGT) as a reproductive technology to prevent the transmission of genetic anomalies to offspring has been available for decades. In the Netherlands, a National Indications Committee was tasked with guiding decisions on using PGT from 2009. The multidisciplinary Committee employs a per-indication approach for evaluating conditions caused by specific pathogenic variants, using a decisional framework, and arrives at its advice through discussion. This paper reflects on the Committee's journey in safeguarding the ethical and societal acceptability of the use of PGT in the Netherlands. We performed a quantitative and qualitative analysis of relevant documentation of the Committee, issued between 2009 and 2024. The Committee advised positively on applying PGT for 134 of 192 (70%) indications. Its advice was based on the criteria 'severity and nature of the disease', 'risk' and 'treatment options' for the majority of indications. Only in a few cases, the Committee make a normative statement about severity. There was no trend observed in requests over the years and the Committee's modus operandi remained consistent. In 15 years, the Committee has shaped the application of PGT for a broad variety of genetic conditions. Through its per-indication approach, it has been able to assess a complex interplay of disease characteristics and provide consistent guidance to medical practitioners in decision-making about the use of PGT. It has served as a robust model to safeguard the ethical and societal acceptability of PGT for a future in which new and rare genetic conditions will continuously be identified.
Zanotti S, Magri F, Salani S
… +15 more, Napoli L, Ripolone M, Pagliarani S, Ronchi D, Fortunato F, Ciscato P, Cassandrini D, Fattori F, D'Angelo MG, Albamonte E, Nigro V, Sciacco M, Corti S, Comi GP, Piga D
Eur J Hum Genet
· 2026 May · PMID 41851258
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Core myopathies are congenital diseases with clinical, pathological and genetic heterogeneity. Main histological features are fiber "cores" showing a focally reduced oxidative enzyme activity. Dusty Core Disease (DuCD) d...Core myopathies are congenital diseases with clinical, pathological and genetic heterogeneity. Main histological features are fiber "cores" showing a focally reduced oxidative enzyme activity. Dusty Core Disease (DuCD) differs from Central Core Myopathy for the presence of irregular areas, without clear borders and round/ovoidal shape, and myofibrillar disorganization characterized by reddish purple granular material depositions. This disorder is defined clinically by severe phenotypes with early onset of disease and molecularly by low level of RyR1 in muscle. Until now DuCD was associated only to biallelic recessive RYR1 mutations. We analyzed the clinical aspects, pathological features and mutational spectrum of four DuCD patients, belonging to our cohort of Congenital Myopathy probands. Molecular analysis detected 5 different RYR1 pathogenic variants, two of them so far unreported. Patients presented a heterogeneous phenotype ranging from severe recessive infantile forms to moderate dominant adult-onset presentations. Histological, immunological and ultrastructural techniques were employed to validate these dominant cases, which expand our knowledge on the inheritance of this subgroup of diseases.
Ghali N, Angwin C, Liebert S
… +14 more, Deaner A, von Klemperer K, Wheeldon N, Johnson D, Sobey G, Samani NJ, Webb TR, Baranowska A, Velvet A, Keigwin S, Baker D, Read K, van Dijk FS, Adlam D
Eur J Hum Genet
· 2026 Jun · PMID 41845085
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Spontaneous coronary artery dissection (SCAD) is a cause of acute myocardial infarction predominantly affecting adult women. A proportion of SCAD cases are associated with rare heritable connective tissue disorders. Vasc...Spontaneous coronary artery dissection (SCAD) is a cause of acute myocardial infarction predominantly affecting adult women. A proportion of SCAD cases are associated with rare heritable connective tissue disorders. Vascular EDS (vEDS), due to deleterious variants in COL3A1, is one of the most common of these. Our aim was to identify specific features of SCAD in vEDS which may aid patient selection for genetic testing. A systematic review of published cases of individuals with SCAD and vEDS was conducted. Additionally, patients with SCAD and genetically confirmed vEDS (SCAD-vEDS) were identified through the UK national EDS service and UK SCAD registry. Data were collected on presentation, management and extra-cardiac findings. Angiography was compared with an age and sex-matched, exome sequenced, control cohort with SCAD but without vEDS (SCAD-nonvEDS). Data from ten SCAD-vEDS patients were identified. There was a lower average age of SCAD and higher proportion of males in individuals with SCAD-vEDS, however differences should be interpreted carefully given cohort size. Fifty-six cases of SCAD-vEDS were identified through systematic review. Systemic features were present in most but not all cases. This report presents a new, angiographically characterised case-control cohort along with a systematic review of the current literature. Whilst clinical differences appear between the SCAD-vEDS and SCAD-nonvEDS groups, these are insufficient to accurately distinguish SCAD-vEDS from the general SCAD population. All individuals with SCAD should be evaluated for underlying vEDS but clinical assessment will miss some cases. Wider genetic testing in some SCAD patients may be merited to enable appropriate management. Systematic review registration: https://www.crd.york.ac.uk/prospero/536751 Identifier: 536751.
Classifying germline variants in hereditary cancer genes remains challenging and requires integrating diverse lines of evidence. BoostDM is a computational method originally developed to identify somatic cancer driver mu...Classifying germline variants in hereditary cancer genes remains challenging and requires integrating diverse lines of evidence. BoostDM is a computational method originally developed to identify somatic cancer driver mutations by detecting signals of positive selection. Given the functional overlap between somatic and germline pathogenic variants in cancer genes, we evaluated the utility of BoostDM for interpreting germline variants in hereditary cancer genes. We assessed BoostDM's performance across six genes with dual roles in sporadic and hereditary cancer (ATM, BRCA1, BRCA2, CDH1, PTEN, TP53), using gene-specific BoostDM models. A total of 1275 germline single nucleotide variants with expert-reviewed pathogenic and benign classifications were included. BoostDM scores were compared to those from AlphaMissense and REVEL, two leading pathogenicity predictors for missense variants. BoostDM correctly classified 74.5% of pathogenic/likely pathogenic and 98.6% of non-synonymous benign/likely benign variants overall. It performed particularly well for non-synonymous, non-missense variants (92.3% sensitivity). For missense variants, BoostDM correctly identified 46% of pathogenic and 95.5% of benign variants. While BoostDM did not outperform AlphaMissense or REVEL, it demonstrated high specificity (99.5%) and positive predictive value (PPV = 98%) for missense variants with high scores ( > 0.5). Gene-specific performance varied, with TP53 showing the most robust results. In conclusion, BoostDM predictions are not a replacement for ACMG/AMP-guided germline variant classification, especially for missense changes. However, its high specificity and PPV suggest that high BoostDM scores can provide supportive evidence of pathogenicity, prompting further clinical and functional investigation.
Munté E, Rofes P, Millán-Castillo M
… +16 more, Solanes A, Muñoz X, Campos O, Alay A, Ajenjo-Bauza M, Navarro E, de la Morena-Barrio B, Salinas M, Vargas-Parra G, Cuesta R, Moreno-Cabrera JM, Cordero D, Pineda M, Del Valle J, Lázaro C, Feliubadaló L
Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS ad...Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.
López-López L, Lapeña-Gil L, Benítez Y
… +9 more, Serrano C, Sánchez-Barbero AI, Blanco-Kelly F, López-Grondona F, Tahsin-Swafiri S, Lorda-Sánchez I, Ayuso C, Mínguez P, Almoguera B
Eur J Hum Genet
· 2026 May · PMID 41826713
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The broad genetic heterogeneity of neurodevelopmental disorders (NDDs) makes their molecular diagnosis particularly challenging. In this context, Whole-Exome Sequencing (WES), specifically in a trio-based design, is a po...The broad genetic heterogeneity of neurodevelopmental disorders (NDDs) makes their molecular diagnosis particularly challenging. In this context, Whole-Exome Sequencing (WES), specifically in a trio-based design, is a powerful strategy due to its ability to detect de novo variants, which are a major contributor to NDDs. However, its clinical implementation is often limited by its associated cost. In this study, we applied a sequential diagnostic workflow to a cohort of 221 individuals with syndromic NDDs and prior negative results from targeted sequencing. The workflow integrates initial solo-WES, followed by a second-tier trio-WES using pooled parental DNA (trio pooled-WES). Overall, this workflow achieved a diagnostic yield of 20.98% and led to the identification of 13 novel candidate genes. The pooling strategy was optimized and validated, demonstrating that trio pooled-WES retains the main advantages of conventional trio-WES while substantially reducing sequencing costs. These results support its implementation as a clinically applicable approach for the genetic diagnosis of NDDs.