European Journal of Human Genetics最新文献

{"title":"5q31 duplications encompassing PURA are associated with a neurodevelopmental disorder.","authors":"Laurine Challeat, Solène Remize, Tarek Alouane, David Laurenceau, Chloé Boisseau, Catherine Hubert, Noémie Celton, Nathalie Le Du, Sandrine Vonwill, Camille Gevrin, Lara Kerbellec, Céline Pebrel-Richard, Matthieu Egloff, Caroline Navarro, Isabelle Perthus, Tanguy Niclass, Roseline Caumes, Jade Fauqueux, Médéric Jeanne, Thomas Smol, Frédéric Laumonnier, Marie-Laure Vuillaume","doi":"10.1038/s41431-026-02230-7","DOIUrl":"https://doi.org/10.1038/s41431-026-02230-7","url":null,"abstract":"<p><p>PURA heterozygous microdeletions and pathogenic variants have been previously associated with neurodevelopmental disorders (NDDs), grouped into PURA-NDDs, characterized by severe neonatal hypotonia, feeding difficulties, developmental delay, intellectual disability, epilepsy, and distinctive facial features. Here we report four individuals carrying overlapping 5q31 duplications encompassing PURA, in addition to five cases from the DECIPHER database and one previously described in the literature. All patients share common features including developmental delay and mild to moderate intellectual disability. The minimal region of overlap spans 215 kb and contains only the PURA gene, suggesting PURA as the candidate gene underlying the observed phenotype. Using transcriptomic and biochemical analyses on cultured lymphocytes from one patient, we found that 5q31 duplication causes a significant upregulation of PURA mRNA and PURA protein, respectively. RNA Sequencing also revealed dysregulated expression of various genes involved in human pathology, especially in neurodevelopmental disorders characterized by intellectual disability. Using primary hippocampal neuronal cultures from mouse embryos, we demonstrated that PURA overexpression impairs neuronal morphology in vitro, inducing a reduction in dendritic arborization and in dendritic spine density. Our findings support that 5q31 duplications encompassing PURA represent a novel genomic disorder presenting with a milder phenotype than the reciprocal deletion syndrome and implicate PURA dosage dysregulation as a key contributor to the associated clinical features.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016101","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":"Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.","authors":"Dana Urbatsch, Anburaj Jeyaraj, Shruti Bedekar, Venkatramanan Rao, Shelby C White, Matthew J Thomas, Andrea Garrod, Christina Peroutka, Aakrosh Ratan, Saurabh S Kulkarni","doi":"10.1038/s41431-026-02228-1","DOIUrl":"10.1038/s41431-026-02228-1","url":null,"abstract":"<p><p>Defects in motile cilia cause a range of disorders, including heterotaxy (HTX), congenital heart disease (CHD), and primary ciliary dyskinesia (PCD). Although these conditions often co-occur, the genetic and mechanistic bases for tissue-specific manifestations remain poorly understood. Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD. Whole-genome sequencing revealed a maternally inherited canonical splice-site variant (c.648+1 G > A, chr2:227,903,110 G > A (GRCh38)) and a paternally inherited missense variant (c.341 G > A; p.Arg114Gln, chr2: 227,893,818 G > A (GRCh38)), both classified as variants of uncertain significance under ACMG/AMP guidelines. Using Xenopus tropicalis, we show that Daw1 depletion disrupts left-right patterning, cardiac looping, and mucociliary flow, all of which are rescued by wild-type human DAW1. Functional testing of patient alleles showed notable tissue specificity: p.Arg114Gln rescued mucociliary flow but did not restore left-right patterning, while the splice-site variant resulted in a complete loss of function in both contexts. These findings closely match the proband's clinical phenotype and provide strong functional evidence to support reclassifying c.648+1 G > A as likely pathogenic and p.Arg114Gln as a context-dependent hypomorphic allele. This study establishes functional criteria for interpreting DAW1 variants, shows how developmental context clarifies genotype-phenotype relationships, and highlights how in vivo models can support ACMG reclassification of unresolved HTX-related variants.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024350","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":"digitalMLPA EZtec-MS: A new highly multiplexed DNA probe-based technique for neonatal screening.","authors":"Terence Diane Fabella, Joery den Hoed, Eva Maria Cutiongco-de la Paz, Carmencita Padilla, Chris Hettinga, Karel de Groot, Martin Lodén-van Straaten, Tatiana C Santos, Richiel van den Berg, Erik A Sistermans, Jan Schouten","doi":"10.1038/s41431-026-02235-2","DOIUrl":"https://doi.org/10.1038/s41431-026-02235-2","url":null,"abstract":"<p><p>Decreasing DNA sequencing costs has paved the way to the use of next generation sequencing (NGS) to expand the number of conditions tested in routine newborn screening (NBS) programs. Expanding NBS programs by NGS, however, raises technical, ethical and economic concerns that are important for low-middle income countries or countries that are hesitant to use sequencing in a public health setting. qPCR-based DNA analyses have already been implemented in routine NBS programs; however, qPCR cannot be highly multiplexed. digitalMLPA (dMLPA) is a highly multiplexed probe-based DNA technique. Here, we describe the new dMLPA EZtec-MS technique that was specifically developed for use on dried blot spots (DBS) and can target up to 1200 DNA sequences representing different variant types, allowing high-throughput testing of crude DNA extracts prepared from a single DBS punch. The assay was validated using positive DNA samples and crude DNA extracts from DBS of 2069 negatively screened Philippine newborns. The EZtec-MS assay used in this study successfully detected copy number variants, (including complex genomic regions (SMN1/2, HBA1/2)), inversions (F8), methylation (imprinting diseases, Fragile X), single nucleotide variants (including ATP7B, CTNS, MT-RNR1), and low copy number sequences (TRECs for SCID, cytomegalovirus) in a single reaction in both positive DNA and crude DNA extracts from DBS. The results also demonstrated that dMLPA EZtec-MS is a high-throughput method, suitable for DBS, and has a relatively short turn-around time of 36-40 h. Our findings indicate that the dMLPA EZtec-MS technique is a promising versatile tool for DNA-based NBS programs.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024311","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":"NSMCE2 / MMS21 structural variant causes chromosome breakage syndrome with primordial dwarfism and severe lung disease.","authors":"Tomer Poleg, Noam Hadar, Vadim Dolgin, Ginat Narkis, Monica Neuhaus, Ilana Aminov, Ekaterina Eremenko, Amit Safran, Nadav Agam, Matan M Jean, Ofek Freund, Uriel Wachsman, Bibi Kanengisser-Pines, Lidia Osyntsov, Esther Manor, Ohad S Birk","doi":"10.1038/s41431-026-02222-7","DOIUrl":"https://doi.org/10.1038/s41431-026-02222-7","url":null,"abstract":"<p><p>Primordial dwarfism (PD) is a genetic disorder characterized by severe intrauterine and postnatal growth failure. While some subtypes involve impaired DNA damage responses, the molecular basis of PD remains incompletely defined. We describe two siblings of non-consanguineous Indian-Jewish ancestry with a likely autosomal recessive syndrome featuring borderline intrauterine growth restriction, severe postnatal growth restriction, hypotonia, consistent dysmorphic features (elongated face, low-set ears, hypotelorism, prominent nose), hypothyroidism, late-onset insulin-dependent diabetes, borderline immune dysregulation, and recurrent pneumonia with interstitial lung disease, leading to death in adolescence. Karyotype and microarrays were normal, but cytogenetic analysis of PHA-stimulated lymphocytes revealed spontaneous chromosomal breakage and polyploidy, without hypersensitivity to cross-linking agents. Linkage analysis, whole genome sequencing, and Manta structural variant calling identified a homozygous tandem duplication within NSMCE2, NC_000008.11(NM_173685.4:c.265-11431_418+8879dup), validated by PCR and Sanger sequencing. RT-PCR of lymphoblastoid cells confirmed an aberrant transcript, predicted to cause a frameshift, premature stop codon, and loss of the SUMO domain. NSMCE2 encodes a core component of the SMC5/6 complex, essential for chromosome structure and repair. Only one prior report has linked NSMCE2 mutations to PD. Our findings determine the clinical and molecular spectrum of this severe chromosome breakage syndrome with PD, lung fibrosis, immune-endocrine abnormalities, and early lethality.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016104","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":"The difficulties of developing guidelines for rare disease: where consensus, evidence-based medicine and screening principles conflict.","authors":"Andrew Latchford, Terri McVeigh","doi":"10.1038/s41431-026-02241-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02241-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016211","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":"Prevalence and penetrance of heritable retinoblastoma in two adult population cohorts: implications for genomic newborn screening.","authors":"Isabella-Anna Lazaridi, Timothy Hall, Helen Hanson, James Fasham, Emma L Baple, Michael N Weedon, Caroline F Wright, Leigh Jackson","doi":"10.1038/s41431-026-02231-6","DOIUrl":"https://doi.org/10.1038/s41431-026-02231-6","url":null,"abstract":"<p><p>Retinoblastoma (Rb) is a rare childhood eye cancer. Almost half of cases are heritable, associated with germline RB1 pathogenic variants that pre-dispose to Rb and extraocular cancers. This study aimed to investigate the prevalence and penetrance of RB1-heritable Rb in two adult population cohorts. We screened participants with whole genome sequencing in the UK Biobank (UKB) (n = 490,413) and All of Us (AoU) (n = 317,964) cohorts for predicted loss-of-function (pLoF) and/or ClinVar pathogenic/likely pathogenic RB1 variants. Electronic health records and questionnaires were used to screen participants for Rb-associated features. In the UKB we generated a stringent and permissive phenotype category, ranging from Rb to Rb-associated extraocular cancers; in AoU we included participants with Rb or ocular cancer. A total of 21 pathogenic pLoF RB1 variants were detected in the UKB (n = 12) and AoU (n = 13) participants. In the UKB, only 25.0% (3/12) of variant carriers reported developing Rb by the age of 60, increasing to 50.0% when including ocular/extraocular cancers. Similarly, 30.8% (4/13) AoU participants developed Rb and/or ocular cancer by the age of 60. Overall, this results in a combined penetrance estimate of 28.0% (7/25). We found 21 and 28 individuals with Rb in the UKB and AoU, respectively, which is consistent with published prevalence estimates, suggesting these cohorts are not depleted of Rb cases. Notably, the penetrance of pathogenic RB1 variants in >800,000 clinically unselected adults was substantially lower than the near complete penetrance reported in clinical cohorts. This has important implications for counselling families following a positive newborn screening result.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001498","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":"Penetrance, effect and causal attribution: which number should be reported for recurrent copy-number variants?","authors":"Himanshu Goel","doi":"10.1038/s41431-026-02236-1","DOIUrl":"https://doi.org/10.1038/s41431-026-02236-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001442","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":"Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.","authors":"Florencia Haase, Oselyne T W Ong, Irene Valenzuela, Adam M Bournazos, Zainab Amasseri, Frenny Sheth, Jayesh Sheth, Harsh Sheth, Rebecca Buchert, Tobias B Haack, Joris Andrieux, Thomas Liehr, Alma Kuechler, Daniel de Los Reyes Helices, Jessica Merjane, Sandra T Cooper, Taroh Kinoshita, Yoshiko Murakami, Richard Webster, Wendy Gold, Leszek Lisowski","doi":"10.1038/s41431-026-02223-6","DOIUrl":"https://doi.org/10.1038/s41431-026-02223-6","url":null,"abstract":"<p><p>Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are essential for neuronal development, synaptic organization and signaling. Defects in GPI-anchor biosynthesis or remodeling cause rare neurodevelopmental disorders, including post-GPI attachment to proteins 1 (PGAP1) deficiency. PGAP1 encodes an inositol deacylase required for GPI-anchor remodeling and appropriate trafficking and membrane localization of GPI-APs. Loss of PGAP1 function disrupts GPI-AP processing, but the clinical spectrum remains incompletely defined because reported cohorts are small. We report 15 individuals with biallelic PGAP1 variants from 11 unrelated families identified through international collaboration. Clinical information was collected using a standardized phenotyping questionnaire and review of available clinical records. The most frequently recorded features were developmental delay or intellectual disability, motor developmental delay, speech impairment, facial dysmorphism, hypotonia and seizures. Independent walking was clearly recorded in a minority of individuals, while feeding, ophthalmological, musculoskeletal and neuroimaging findings were recorded in subsets of the cohort. Clinical investigations were performed as part of routine care and were not uniform across sites. Accordingly, source-dependent assessments including MRI, EEG, EMG/NCS, formal ophthalmology, hearing assessment, systemic imaging, IQ/DQ testing, MRC scoring and anthropometric Z-scores are reported descriptively or using available-data denominators. Spasticity, hypertonia or possible peripheral nerve involvement was recorded in some clinical summaries; however, electrophysiological confirmation was not uniformly available, and confirmed peripheral neuropathy was not analyzed as a cohort-level prevalence outcome. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-APs, supporting impaired GPI-anchor remodeling. These findings expand the genotypic and recorded phenotypic spectrum of PGAP1 deficiency.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988618","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":"Global recommendations for the use of diagnostic genomic sequencing in the prenatal setting on behalf of the ESHG and ISPD.","authors":"Zandra C Deans, Lina Basel Salmon, Kwong Wai Choy, Guido de Wert, Zirui Dong, Lilian Downie, Francesca Romana Grati, Sabine Hentze, Paula Jorge, Brynn Levy, Luca Lovrecic, Dora Mayen, Álvaro Mendes, Michael Morris, Ashley Pritchard, Raquel Gouveia Silva, Tina-Marié Wessels, Francesca Forzano, Natalie J Chandler","doi":"10.1038/s41431-026-02217-4","DOIUrl":"https://doi.org/10.1038/s41431-026-02217-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976340","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":"Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series.","authors":"Marianthi Karali, Susanne Kohl, Francesco Testa, Eleanor Hay, Yasas D Kolambage, German Demidov, Tobias Haack, Hamid Ghaedi, Siying Lin, Gemma Natale, Vindya Subasinghe, Pyara Rathnayake, Sarah Wörz, Gavin Arno, Rebecca Buchert, Katarina Stingl, Francesca Simonelli, Sandro Banfi","doi":"10.1038/s41431-026-02232-5","DOIUrl":"https://doi.org/10.1038/s41431-026-02232-5","url":null,"abstract":"<p><p>Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982463","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}