European Journal of Human Genetics最新文献

{"title":"Consensus recommendations for next-generation sequencing-based genetic testing in Rare Neurological diseases","authors":"Aleš Maver, Katja Lohmann, Lena-Marie Urbanczyk, Astri Arnesen, Ivo Barić, Peter Bauer, Kailash P. Bhatia, Sylvia Boesch, Fran Borovečki, Norbert Brüggemann, Zih-Hua Fang, Heinz Gabriel, Tobias B. Haack, Henry Houlden, Milena Janković, Erik-Jan Kamsteeg, Michelangelo Mancuso, Deborah Mascalzoni, Maria Judit Molnar, Alexander Münchau, Kornelia Neveling, Ivana Novaković, Borut Peterlin, Ludger Schols, Nika Schuermans, Katie Shiels, Marc Sturm, Rachel Taylor, Marina A. J. Tijssen, Lisenka E. L. M. Vissers, Victoria Williams, Holm Graessner, on behalf of the European Reference Network for Rare Neurological Disorders (ERN-RND)","doi":"10.1038/s41431-026-02198-4","DOIUrl":"10.1038/s41431-026-02198-4","url":null,"abstract":"We recently established an external quality assessment (EQA) scheme for next-generation sequencing (NGS) diagnostics in rare neurological disorders (RND) in collaboration with the EMQN. The first assessment rounds revealed limitations and variability in the quality and completeness of genetic testing reports. To improve and harmonize reporting in NGS-based diagnostics for RND, we identified 28 topics requiring recommendations based on EQA findings. These topics were grouped into four areas: clinical information, interpretation, methodology, and reporting. A team of 31 experts with relevant expertise was formed. Using an adapted Delphi approach, two rounds of surveys were conducted to prioritize the topics. Subsequently, area-specific expert groups met to formulate recommendations, followed by a final approval round using the five-finger consensus method involving all experts. In both Delphi rounds, all topics were rated as either very important (n = 12) or important (n = 16), and all were advanced for recommendation development. Consensus recommendations were achieved for 27 of the 28 topics. These include guidance on gene panel composition and updating, addressing disease-specific limitations of NGS (e.g., repeat expansion disorders), defining minimal quality parameters, and promoting sharing of variant interpretations. Each recommendation is supported by real-world examples. Due to differences in national healthcare frameworks and policies, consensus could not be reached regarding which patients should or should not undergo NGS testing. The dissemination of these recommendations is expected to improve the quality of genetic testing and reporting in RND diagnostics, promoting harmonization across laboratories and enabling easier comparison and interpretation of genetic testing reports.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1503-1512"},"PeriodicalIF":4.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02198-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report","authors":"Sean W. Willemse, Koen C. Demaegd, Wouter Koole, Ruben P. A. van Eijk, Wouter van Rheenen, Jan H. Veldink, Leonard H. van den Berg, Michael A. van Es","doi":"10.1038/s41431-026-02208-5","DOIUrl":"10.1038/s41431-026-02208-5","url":null,"abstract":"The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1590-1594"},"PeriodicalIF":4.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Further characterization of the BRSK2-associated neurodevelopmental disorder.","authors":"Palak Singhal, Tzung-Chien Hsieh, Nadja Ehmke, Elena Bacchelli, Marta Viggiano, Elena Maestrini, Paola Visconti, Annio Posar, Maria Cristina Scaduto, Alessandro Vaisfeld, Carey Ronspies, Sarah Burke, Joana Rosmaninho Salgado, Joaquim Sá, Sara Ribeiro, Amelle Shillington, Anjali Aggarwal, Christina Dailey, Carol Saunders, Florencia Del Viso, Chaya N Murali, Melissa MacPherson, Oana Caluseriu, Alain Verloes, Jonathan Levy, Yline Capri, Hannah S Kemmer, Manuel Holtgrewe, Philip M Boone, Lance Rodan, Georgia Vasileiou, Melissa Pauly, André Reis, Isabella Herman, Ivy Johnson, Himanshu Goel, Ana Maria Rodriguez Barreto, Flavio Faletra, Catia Mio, Mona L Essawi, Heba A Hassan, Wessam E Sharaf-Eldin, Nirmeen Kishk, Giuseppe Donato Mangano, Renata Mangano, Andrea K Shields, Judith D Ranells, Trine Bjørg Hammer, Clara Velmans, Christian Netzer, Nora Winnerling, Konstantinos Kolokotronis, Benjamin Seidl, Anita Rauch, Alberto Fernandez-Jaen, Aboulfazl Rad, Gabriela Oprea, Paskal Cullufi, Sonila Tomori, Claire Beneteau, Marine Legendre, Caroline Rooryck, Hannah Klinkhammer, Tobias B Haack, Amjad Khan, Johanna Kick, Deborah Bartholdi, Dominique Braun, Erin E Baldwin, David H Viskochil, Lorenzo D Botto, Anna LaGroon, Emily Black, Kameryn M Butler, Emmanuelle Ranza, Manon Macherel, Vincent Desportes, Mathilde Pujalte, Louis Januel, Boris Keren, Cyril Mignot, Madeleine Harion, Maartje L E Voors, Charlotte W Ockeloen, Javier Porta-Pelayo, Bernt Popp, Peter Krawitz, Heinrich Sticht, Anne Gregor, Christiane Zweier","doi":"10.1038/s41431-026-02195-7","DOIUrl":"https://doi.org/10.1038/s41431-026-02195-7","url":null,"abstract":"<p><p>Variants in BRSK2, encoding brain specific kinase-2, have recently been associated with an autosomal dominant neurodevelopmental disorder (NDD). We have assembled 52 cases with heterozygous BRSK2 variants and variable neurodevelopmental phenotypes with frequent neuropsychiatric and behavioral symptoms. The variant spectrum included 15 different truncating variants, seven (potential) splice variants, three structural variants, and 12 different missense variants. Of the missense variants, seven were in the kinase domain, and the others in the UBA and the KA1 domain or outside domains. Variants occurred de novo in 19 cases and were inherited in 18. We utilized Drosophila melanogaster as a model and assessed viability and performed climbing and bang sensitivity assays upon knockdown of the fly orthologue sff or upon overexpression of wildtype or mutant human BRSK2. Pan-neuronal knockdown of sff resulted in impaired locomotor behavior and seizure susceptibility. Ubiquitous or pan-neuronal overexpression of human wildtype BRSK2 in Drosophila resulted in lethality or locomotor impairment, respectively, indicating toxicity. Overexpressing mutant BRSK2 did not or incompletely affect viability and locomotor behavior for six of seven tested kinase domain missense variants and one KA1 domain variant, indicating a (partial) loss-of-function effect. Interestingly, overexpressing BRSK2 with the remaining missense variant from the kinase domain and the two most C-terminal missense variants resulted in possible gain of function. Our findings further delineate the clinical and molecular spectrum of BRSK2-associated NDD and provide further insights into the role of BRSK2/sff in nervous system function and dysfunction.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaling up genomic newborn screening: implementation lessons from the BabyScreen+ study.","authors":"Nathasha Kugenthiran, Erin Tutty, Anaita Kanga-Parabia, Jade Caruana, Katrina Scarff, Nitzan Lang, Lilian Downie, Sebastian Lunke, Alison D Archibald, Zornitza Stark, Stephanie Best","doi":"10.1038/s41431-026-02192-w","DOIUrl":"https://doi.org/10.1038/s41431-026-02192-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling missing variants through target capture-based long-read sequencing in autosomal recessive disorders.","authors":"Jee-Soo Lee, Kyeong Seon Ryu, Hyesu Lee, Hara Lim, Seonhoo Youn, Hansol Lim, Seung Won Chae, Hobin Sung, Sung Im Cho, Yeseul Kim, Joo Won Jang, Hoyeon Lee, Jin Sook Lee, Jung Min Ko, Jong-Hee Chae, Moon-Woo Seong","doi":"10.1038/s41431-026-02197-5","DOIUrl":"https://doi.org/10.1038/s41431-026-02197-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Who and how we engage: A systemic mapping of stakeholder perspectives on genomic newborn screening.","authors":"Amicia Phillips, Kate Lyle, Dahria Kuyser, Anneke Lucassen, Caroline F Wright, Leigh Jackson","doi":"10.1038/s41431-026-02185-9","DOIUrl":"https://doi.org/10.1038/s41431-026-02185-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate.","authors":"Yao Yu, Gabriel J Kowalczyk, Chad D Huff, Jacqueline T Hecht, Ariadne Letra","doi":"10.1038/s41431-026-02189-5","DOIUrl":"https://doi.org/10.1038/s41431-026-02189-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic discovery of structural variants causing foveal hypoplasia using SVRare and long-read nanopore sequencing","authors":"Mohammed A. M. Derar,&nbsp;Jing Yu,&nbsp;Christopher M. Watson,&nbsp;Martin McKibbin,&nbsp;Sandra M. Bell,&nbsp;Chris F. Inglehearn,&nbsp;Carmel Toomes","doi":"10.1038/s41431-026-02190-y","DOIUrl":"10.1038/s41431-026-02190-y","url":null,"abstract":"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.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1493-1502"},"PeriodicalIF":4.6,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02190-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harmonising the scope of practice for genetic counsellors in the D-A-CH region: a cross-border consensus for Germany, Austria, and Switzerland","authors":"Gunda Schwaninger,&nbsp;Kathrin Taxer,&nbsp;Wera Hofmann,&nbsp;Christophe Cordier,&nbsp;Camila Gabriel,&nbsp;Johanna Tecklenburg,&nbsp;Johannes Zschocke,&nbsp;Simone Heidemann","doi":"10.1038/s41431-026-02188-6","DOIUrl":"10.1038/s41431-026-02188-6","url":null,"abstract":"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","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 10","pages":"1524-1528"},"PeriodicalIF":4.6,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-026-02188-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-year experience of a combined newborn screening for spinal muscular atrophy and severe combined immunodeficiency in Liguria, Italy.","authors":"Concetta Aloi, Monica Traverso, Alessandro Salina, Marco Di Duca, Michela Cassanello, Stefania Bertoni, Stefano Volpi, Serena Palmeri, Marina Pedemonte, Noemi Brolatti, Barbara Tappino, Federica Lanza, Maura Faraci, Marco Gattorno, Federico Zara, Claudio Bruno, Mohamad Maghnie","doi":"10.1038/s41431-026-02183-x","DOIUrl":"https://doi.org/10.1038/s41431-026-02183-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}