Lea Rodriguez, Bernard Leroy, Franck Toledo, Julianne Susanne Funk, Thorsten Stiewe, Panagiotis Baliakas, François Delhommeau, Thierry Soussi
{"title":"Low-penetrance TP53 variants are mainly hypomorphic: an underestimated issue with high clinical significance.","authors":"Lea Rodriguez, Bernard Leroy, Franck Toledo, Julianne Susanne Funk, Thorsten Stiewe, Panagiotis Baliakas, François Delhommeau, Thierry Soussi","doi":"10.1038/s41525-026-00568-x","DOIUrl":"10.1038/s41525-026-00568-x","url":null,"abstract":"<p><p>Missense mutations that inactivate p53 are common in cancer. LiFraumeni syndrome, which is linked to early-onset cancer, is caused by germline mutations in TP53. Full-penetrant, inactive variants have garnered great attention, whereas low-penetrant variants are less well understood despite their clinical importance. This study systematically leveraged the 2025 UMD_TP53 database to identify missense variants that exhibit a statistically skewed germline-versus-somatic ratio (GVSr). Unlike classic hotspots that are equally prevalent in somatic and germline settings, these variants were disproportionately found in the germline, suggesting they act as low-penetrance variants with insufficient potency to drive tumorigenesis as single somatic events. To define the biological basis of LPVs, we integrated functional data from multiplexed assays of variant effects, tumor cell transcriptome analyses and computational predictive tools. This characterization revealed that these high-GVSr p53 variants consistently retain intermediate transcriptional activity and growth-suppressive function, classifying them distinctively as hypomorphic alleles rather than loss-of-function mutants. Our findings highlight the complexity of TP53 variant effects and underscore the importance of refined functional classification. Recognizing and accurately characterizing hypomorphic variants associated with low-penetrance cancer risk are essential for precision oncology, as they will improve genetic counseling, risk stratification, and tailored surveillance strategies for individuals with TP53 mutations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junko Tsuji, Micah Rickles-Young, Justin Abreu, Alyssa Friedman, Caroline Petersen, J Bryan, Konrad Scheffler, Taylor O'Connell, Theo Heyns, Edyta Malolepsza, Mark Fleharty, Katie Larkin, Kenneth J Livak, Shuqiang Li, David A Reardon, Catherine J Wu, Patrick A Ott, Fanny Dao, Heidi Rehm, Max Jan, Chip Stewart, Gad Getz, Varun Jain, Severine Catreux, Carrie Cibulskis, Niall Lennon
{"title":"Clinical validation of a high-performance somatic exome sequencing assay: from target-enrichment strategy to variant calling.","authors":"Junko Tsuji, Micah Rickles-Young, Justin Abreu, Alyssa Friedman, Caroline Petersen, J Bryan, Konrad Scheffler, Taylor O'Connell, Theo Heyns, Edyta Malolepsza, Mark Fleharty, Katie Larkin, Kenneth J Livak, Shuqiang Li, David A Reardon, Catherine J Wu, Patrick A Ott, Fanny Dao, Heidi Rehm, Max Jan, Chip Stewart, Gad Getz, Varun Jain, Severine Catreux, Carrie Cibulskis, Niall Lennon","doi":"10.1038/s41525-026-00569-w","DOIUrl":"10.1038/s41525-026-00569-w","url":null,"abstract":"<p><p>Clinical whole-exome sequencing (WES) has revolutionized clinical diagnostics by enabling scalable, cost-effective molecular profiling to detect somatic variants and identify novel therapeutic targets. In particular, the clinical evaluation of somatic variants relies on both high-quality sequencing data and robust variant detection with rapid turnaround times. We developed an updated WES workflow utilizing a co-developed Twist Bioscience targeting panel and the DRAGEN (Dynamic Read Analysis for GENomics) platform, benchmarked with cell line mixtures containing >40,000 simulated variants and a clinical cohort of FFPE tumor specimens. Our assay, the Broad Clinical Somatic Whole Exome Assay V6.0, demonstrated high sensitivity (96.9% for SNVs with variant allele fraction [VAF] >10% at ≥125X; 93.5% for InDels with VAF > 20% at ≥125X) and low false positive rates (0.04 and 0.01 per Mb, respectively). The assay meets clinical requirements and enables large-scale, accurate variant profiling of cancers, expanding opportunities for molecular diagnostics across diverse clinical settings.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Riccardo Sangermano, Kaoru Fujinami, Suk Ho Byeon, Emily M Place, Julien Navarro, Johanna Valensi, Samer Khateb, Eyal Banin, Christel Condroyer, Stephanie DiTroia, Dror Sharon, Christina Zeitz, Isabelle Audo, Kinga M Bujakowska, Jinu Han
{"title":"Variants in the ciliopathy gene SCLT1 are associated with non-syndromic and syndromic retinal degeneration of variable severity.","authors":"Riccardo Sangermano, Kaoru Fujinami, Suk Ho Byeon, Emily M Place, Julien Navarro, Johanna Valensi, Samer Khateb, Eyal Banin, Christel Condroyer, Stephanie DiTroia, Dror Sharon, Christina Zeitz, Isabelle Audo, Kinga M Bujakowska, Jinu Han","doi":"10.1038/s41525-026-00566-z","DOIUrl":"10.1038/s41525-026-00566-z","url":null,"abstract":"<p><p>Inherited retinal degenerations (IRDs) are a group of clinically and genetically heterogeneous blinding disorders. In this study, we describe five families clearly or which were presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD, in which affected probands carried rare bi-allelic variants in SCLT1, a gene previously associated with multiple autosomal recessive ciliopathies. Eight of the ten variants identified were novel; five variants affected splicing, including the known missense p.(Lys544Arg), detected in compound heterozygosity in three East Asian probands, and the novel, hypomorphic, deep-intronic variant c.290+2732A>G, leading to the inclusion of a 45-bp cryptic exon containing a premature termination codon. Analysis of the genomic data also revealed a large in-frame tandem duplication spanning exons 3-10, which was subsequently validated. Although no clear correlation was found between the severity of the SCLT1-associated phenotypes and the identified causal variants, this report expands the current knowledge of SCLT1-associated disease by enriching its mutational landscape and clearly supports its association with autosomal recessive non-syndromic IRD.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fulya Akçimen, Monica Diez-Fairen, Ignacio Alvarez, Victor Puente, Spencer Grant, Jorge Hernandez-Vara, Marzieh Khani, Mariateresa Buongiorno, Félix Javier Jiménez-Jiménez, José A G Agúndez, Miquel Aguilar, Esther Cubo, Jesus Perez, Javier Pagonabarraga, Núria Caballol, Asuncion Avila, Jinhui Ding, Elena García-Martín, Hortensia Alonso-Navarro, Yaroslau Compta, Carlos Cruchaga, Katrin Beyer, J Raphael Gibbs, Andrew Singleton, Sara Bandres-Ciga, Pau Pastor
{"title":"Unraveling the genetic architecture of non-Huntington chorea: a biobank-scale study of rare variants and repeat expansions.","authors":"Fulya Akçimen, Monica Diez-Fairen, Ignacio Alvarez, Victor Puente, Spencer Grant, Jorge Hernandez-Vara, Marzieh Khani, Mariateresa Buongiorno, Félix Javier Jiménez-Jiménez, José A G Agúndez, Miquel Aguilar, Esther Cubo, Jesus Perez, Javier Pagonabarraga, Núria Caballol, Asuncion Avila, Jinhui Ding, Elena García-Martín, Hortensia Alonso-Navarro, Yaroslau Compta, Carlos Cruchaga, Katrin Beyer, J Raphael Gibbs, Andrew Singleton, Sara Bandres-Ciga, Pau Pastor","doi":"10.1038/s41525-026-00567-y","DOIUrl":"10.1038/s41525-026-00567-y","url":null,"abstract":"<p><p>Chorea can arise from genetic, metabolic, pharmacologic, and autoimmune causes. In clinical practice, however, non-genetic causes are rare. The most common genetic cause is a CAG repeat expansion in HTT, leading to Huntington's disease (HD). Beyond HD, systematic studies have been lacking and many individuals with non-HD chorea remain without a molecular diagnosis. We conducted whole-exome and genome sequencing analysis on 190 non-HD chorea cases, leveraging data from the All of Us Research Program (n = 134), UK Biobank (n = 26), and a clinically ascertained multicenter Spanish cohort recruited by the Spanish Study Group for Genetics of Chorea (SSGGC) (n = 30). Variant calling was performed without pre-filtering based on a disease or gene list, and variants were clinically contextualized using OMIM, ClinVar, and in silico predictions. We identified thirteen protein-altering variants, including six previously described as pathogenic or likely pathogenic. Notably, we identified a pathogenic JPH3 expansion in a patient of Black race and c9orf72 expansions in individuals of European and South Asian ancestry. These findings explained 23% of cases in the SSGGC, 12% in UK Biobank, and 4% in All of Us. Our results broaden the genetic architecture of non-HD chorea and highlight the value of multi-ancestry genomic approaches for rare movement disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13243629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa A Lansdon, Byunggil Yoo, Ayse Keskus, Irina Pushel, Chengpeng Bi, Tanveer Ahmad, Asher Bryant, Adam Walter, Margaret Gibson, Mary Rindler, Weijie Li, Sultan M Habeebu, Linda D Cooley, John Herriges, Elena Repnikova, Lei Zhang, Keith J August, Terrie G Flatt, Alan S Gamis, Erin M Guest, J Allyson Hays, Maxine Hetherington, Karen Lewing, Tomi Pastinen, Mikhail Kolmogorov, Midhat S Farooqi
{"title":"Proof-of-concept study for the detection of somatic structural variant driver alterations using HiFi long-read sequencing in a pediatric leukemia cohort.","authors":"Lisa A Lansdon, Byunggil Yoo, Ayse Keskus, Irina Pushel, Chengpeng Bi, Tanveer Ahmad, Asher Bryant, Adam Walter, Margaret Gibson, Mary Rindler, Weijie Li, Sultan M Habeebu, Linda D Cooley, John Herriges, Elena Repnikova, Lei Zhang, Keith J August, Terrie G Flatt, Alan S Gamis, Erin M Guest, J Allyson Hays, Maxine Hetherington, Karen Lewing, Tomi Pastinen, Mikhail Kolmogorov, Midhat S Farooqi","doi":"10.1038/s41525-026-00560-5","DOIUrl":"10.1038/s41525-026-00560-5","url":null,"abstract":"<p><p>Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variants (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs (n = 5/5) detected through routine clinical testing. This approach also identified crSVs that resulted in the classification of a leukemia genetic subtype for four additional patients (n = 4/12), such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, that were missed by routine clinical approaches. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13243536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Felix Boschann, Johannes Kopp, Susanne Römer, Oliver Küchler, Hristiana Lyubenova, Nicolai von Kügelgen, Erik Hertstein, Lea Hagelstein, Christian Becker, Kerstin Becker, Sebastian Brachs, Knut Mai, David Meierhofer, Dominik Seelow, Stefan Mundlos, Denise Horn, Markus Schuelke, Björn Fischer-Zirnsak
{"title":"A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics.","authors":"Felix Boschann, Johannes Kopp, Susanne Römer, Oliver Küchler, Hristiana Lyubenova, Nicolai von Kügelgen, Erik Hertstein, Lea Hagelstein, Christian Becker, Kerstin Becker, Sebastian Brachs, Knut Mai, David Meierhofer, Dominik Seelow, Stefan Mundlos, Denise Horn, Markus Schuelke, Björn Fischer-Zirnsak","doi":"10.1038/s41525-026-00564-1","DOIUrl":"10.1038/s41525-026-00564-1","url":null,"abstract":"<p><p>Pathogenic variants affecting components of the mitochondrial translation machinery lead to various impairments of mitochondrial function and thereby cause a spectrum of multisystem diseases. In an infant with a fatal, metabolic multisystem condition we performed a comprehensive multi-omics approach and detected the intronic biallelic variant NM_014050.4:c.219+6 T > A in MRPL42 (mitochondrial ribosomal protein L42) encoding a component of the large mitochondrial ribosomal subunit. RNA-seq revealed a strong reduction and aberrant splicing of the majority of MRPL42 transcripts leading to a frameshift and thereby to a premature termination codon: p.(Asn46Leufs*18). However, additional use of the canonical splice site led to a low residual expression of the wildtype transcript and MRPL42 protein abundance was consequently strongly reduced. Complex I and IV activity of the oxidative phosphorylation (OXPHOS) system were reduced and a decrease of complex I, III, IV, and mitoribosomal-related proteins was identified by proteomics. Complementation with wildtype MRPL42 corrected most of these phenotypes confirming that they were a direct consequence of the limited availability of MRPL42. Our multi-omics data confirm biallelic MRPL42 loss-of-function as the underlying cause of the fatal mitochondrial disease in our patient. Therefore, we propose MRPL42 deficiency as the cause of a mitochondrial ribosome-related combined OXPHOS-deficiency syndrome.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13057132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Population-scale genomic screening reveals high frequency of actionable secondary findings in Chinese newborns.","authors":"Yushan Huang, Ya Gao, Zonghao Duan, Xiao Jia, Yue Sun, Chunhua Liu, Hui Huang, Junnian Liu, Silin Pan, Xin Jin, Mingyan Fang","doi":"10.1038/s41525-026-00565-0","DOIUrl":"10.1038/s41525-026-00565-0","url":null,"abstract":"<p><p>Secondary findings (SFs) from genome sequencing have significant implications for disease prevention and early intervention, yet their population-specific spectrum remains poorly characterized in non-European cohorts. We performed whole-genome sequencing of 6685 Chinese newborns and evaluated pathogenic variants in 84 genes from the American College of Medical Genetics and Genomics (ACMG) SF v3.3 list according to ACMG/Association for Molecular Pathology (AMP) classification guidelines, and cross-referenced against ClinVar. We identified 306 unique actionable variants, comprising 172 known pathogenic variants (KP) and 134 expected pathogenic variants (EP). When heterozygous carriers of autosomal recessive (AR) variants were included, 9.12% (610/6685) of newborns carried at least one pathogenic variant. Under ACMG SF criteria, clinically actionable variants were identified in 5.06% (338/6685) of newborns, predominantly affecting cardiovascular disease genes (3.49%) and cancer predisposition genes (1.26%), most commonly involving LDLR, TTN, and BRCA2. Importantly, 28 variants across 12 genes showed significant allele frequency divergence between Chinese and European ancestries, highlighting ancestry-specific genetic architecture. Our findings support the inclusion of high-penetrance genes prevalent in East Asian populations in population-tailored genomic screening panels, providing essential reference data for the equitable implementation of precision newborn genomics in underrepresented populations.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13216545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Layla Ahmed, Erika Tavares, Janice Min Li, Kashif Ahmed, Maanik Mehta, Christabel Eileen, Genevieve Ah-Sen, Rahma Osman, Kit Green-Sanderson, Anna Dvaladze, Graeme Nimmo, Ashish R Deshwar, Tara Paton, Guillermo Casallo, Christian R Marshall, Elise Heon, Ajoy Vincent
{"title":"A novel phenotype-guided genome analysis pipeline for variant discovery.","authors":"Layla Ahmed, Erika Tavares, Janice Min Li, Kashif Ahmed, Maanik Mehta, Christabel Eileen, Genevieve Ah-Sen, Rahma Osman, Kit Green-Sanderson, Anna Dvaladze, Graeme Nimmo, Ashish R Deshwar, Tara Paton, Guillermo Casallo, Christian R Marshall, Elise Heon, Ajoy Vincent","doi":"10.1038/s41525-026-00557-0","DOIUrl":"10.1038/s41525-026-00557-0","url":null,"abstract":"<p><p>Inherited retinal dystrophies (IRDs) are a genetically diverse group of vision loss disorders with over 360 implicated genes. However, 30-50% of cases remain unresolved after panel-based clinical testing and may benefit from exome or genome sequencing for a genetic diagnosis. To manage the extensive and analytically demanding datasets generated by genome sequencing, we developed ReDGAP (Retinal Degeneration Genome Analysis Pipeline), a phenotype-guided, semi-automated genome analysis pipeline that integrates clinical phenotyping with flexible variant scoring to prioritize variants of interest ( https://github.com/vincentlab-la/ReDGAP ). The pipeline supports the joint analysis of multiple variant classes, using an evidence-weighted scoring system informed by in silico predictors. Validation in eleven previously solved IRD cases achieved a 100% re-identification rate. Application to five unsolved cases yielded diagnoses in four (80%), including intronic variants in CRB1 and HGSNAT, a tandem duplication in OAT, and a 5'UTR deletion affecting a retina-specific promoter of RPGRIP1. Functional validation confirmed transcript-level disruptions in three variants, while computational analysis demonstrated regulatory impact in the fourth. Integrating phenotypic data with broad variant analysis offers a tailored model for improving IRD diagnostics, enabling timely molecular diagnoses and informing eligibility for emerging gene-targeted therapies. This positions ReDGAP as a tailored, clinically relevant model for investigating rare diseases within the evolving landscape of precision health.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13194906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147574953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J Najera, Y Mavura, A Adhikari, M Kvale, R C Gallagher, N Risch
{"title":"No association between genetic ancestry and exome sequencing-based diagnosis of inborn errors of metabolism.","authors":"J Najera, Y Mavura, A Adhikari, M Kvale, R C Gallagher, N Risch","doi":"10.1038/s41525-026-00562-3","DOIUrl":"10.1038/s41525-026-00562-3","url":null,"abstract":"<p><p>Inborn errors of metabolism (IEMs) are severe genetic disorders caused by disruptions in metabolic pathways, frequently presenting in early life. Exome (ES) and genome (GS) sequencing have revolutionized the diagnostic approach for Mendelian disorders. However, most studies evaluating the diagnostic yield of ES have focused on predominantly European ancestry populations, leaving significant gaps in understanding its efficacy across diverse ancestries. We evaluated the diagnostic yield of ES in a cohort of 845 newborns with clinically diagnosed IEMs through the California Department of Public Health's Genetic Disease Screening Program (GDSP) and its relationship to genetic ancestry. Over 55% of this ancestrally diverse cohort was maternally reported as non-white/European. By estimating genetic ancestry from exome sequencing data, we assessed its relationship with ES diagnostic outcomes. Diagnostic yield by ES did not significantly differ by any genetic ancestry, supporting its equitable performance across all ancestries among these largely recessive disorders. Higher consanguinity coefficients were associated with increased homozygosity among exome-positive cases, without affecting diagnostic yield across genetic ancestries.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13187471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Izabela Broniarek, David J Kwiatkowski, Neil Rajan, Kuniaki Seyama, Marcin Drzewiecki, Ireneusz Stolarek, Luiza Handschuh, Marek Figlerowicz, Piotr Kozlowski, Katarzyna Klonowska
{"title":"Genotype-based prevalence of Birt-Hogg-Dubé syndrome in the healthcare and genomic registry populations - breaking the 'rare disease' status?","authors":"Izabela Broniarek, David J Kwiatkowski, Neil Rajan, Kuniaki Seyama, Marcin Drzewiecki, Ireneusz Stolarek, Luiza Handschuh, Marek Figlerowicz, Piotr Kozlowski, Katarzyna Klonowska","doi":"10.1038/s41525-026-00563-2","DOIUrl":"10.1038/s41525-026-00563-2","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"11 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13031786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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