NPJ Genomic Medicine最新文献_第2页

A biallelic MRPL42 variant causes a combined oxidative phosphorylation deficiency syndrome revealed by multi-omics. 多组学揭示了双等位基因MRPL42变异引起联合氧化磷酸化缺乏综合征。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-04-03 DOI: 10.1038/s41525-026-00564-1

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":"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.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"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}

引用次数: 0

Population-scale genomic screening reveals high frequency of actionable secondary findings in Chinese newborns. 人口规模的基因组筛查显示中国新生儿中可操作的继发发现的频率很高。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-04-02 DOI: 10.1038/s41525-026-00565-0

Yushan Huang, Ya Gao, Zonghao Duan, Xiao Jia, Yue Sun, Chunhua Liu, Hui Huang, Junnian Liu, Silin Pan, Xin Jin, Mingyan Fang

{"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":"https://doi.org/10.1038/s41525-026-00565-0","url":null,"abstract":"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.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel phenotype-guided genome analysis pipeline for variant discovery. 一种用于变异发现的新型表型导向基因组分析管道。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-28 DOI: 10.1038/s41525-026-00557-0

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":"https://doi.org/10.1038/s41525-026-00557-0","url":null,"abstract":"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.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

No association between genetic ancestry and exome sequencing-based diagnosis of inborn errors of metabolism. 遗传血统与基于外显子组测序的先天性代谢错误诊断之间无关联。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-27 DOI: 10.1038/s41525-026-00562-3

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":"https://doi.org/10.1038/s41525-026-00562-3","url":null,"abstract":"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.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genotype-based prevalence of Birt-Hogg-Dubé syndrome in the healthcare and genomic registry populations - breaking the 'rare disease' status? 基于基因型的birt - hogg - dub<s:1>综合征在医疗保健和基因组登记人群中的流行——打破“罕见病”的状态？

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-27 DOI: 10.1038/s41525-026-00563-2

Izabela Broniarek, David J Kwiatkowski, Neil Rajan, Kuniaki Seyama, Marcin Drzewiecki, Ireneusz Stolarek, Luiza Handschuh, Marek Figlerowicz, Piotr Kozlowski, Katarzyna Klonowska

引用次数: 0

Completely resolved structural variants by optical genome mapping with adaptive sampling from CNV discovery. 完全解决结构变异的光学基因组定位与自适应采样从CNV发现。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-26 DOI: 10.1038/s41525-026-00561-4

Li Fu, Chong Ae Kim, Masatoshi Tokita, Yohane Miyata, Nobuhiko Okamoto, Yoshio Makita, Hitoshi Osaka, Ayataka Fujimoto, Atsuro Daida, Jun Nirei, Noriko Udagawa, Seiichi Hayakawa, Kimiko Deguchi, Mitsumasa Fukuda, Hiroshi Matsumoto, Manami Akasaka, Junichiro Okada, Yohei Misumi, Jun Kido, Toshifumi Suzuki, Hiromi Aoi, Rie Seyama, Haruka Hamanoue, Satomi Mitsuhashi, Sachiko Ohori, Ken Saida, Yuta Inoue, Kohei Hamanaka, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Atsuo Itakura, Naoki Harada, Atsushi Fujita, Naomichi Matsumoto

{"title":"Completely resolved structural variants by optical genome mapping with adaptive sampling from CNV discovery.","authors":"Li Fu, Chong Ae Kim, Masatoshi Tokita, Yohane Miyata, Nobuhiko Okamoto, Yoshio Makita, Hitoshi Osaka, Ayataka Fujimoto, Atsuro Daida, Jun Nirei, Noriko Udagawa, Seiichi Hayakawa, Kimiko Deguchi, Mitsumasa Fukuda, Hiroshi Matsumoto, Manami Akasaka, Junichiro Okada, Yohei Misumi, Jun Kido, Toshifumi Suzuki, Hiromi Aoi, Rie Seyama, Haruka Hamanoue, Satomi Mitsuhashi, Sachiko Ohori, Ken Saida, Yuta Inoue, Kohei Hamanaka, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Atsuo Itakura, Naoki Harada, Atsushi Fujita, Naomichi Matsumoto","doi":"10.1038/s41525-026-00561-4","DOIUrl":"https://doi.org/10.1038/s41525-026-00561-4","url":null,"abstract":"Structural variants (SVs), including duplications, deletions, inversions, translocations, and insertions, play major roles in human phenotypic diversity but remain difficult to detect because of variable size and structural complexity. Optical genome mapping (OGM) uses ultra-high molecular weight DNA (>150 kb) fluorescently labeled at a specific six-nucleotide sequence, enabling comprehensive SV detection by analyzing labeling patterns along long DNA molecules. This study aimed to fully characterize SVs using OGM. OGM was applied to 30 cases with exome sequencing-based copy number (CN) variants (16 CN losses, 7 CN gains, and 7 combined CN losses and gains). Additionally, targeted Oxford Nanopore long-read sequencing with adaptive sampling was used to determine breakpoints of SVs. This approach revealed undetected SVs in 14 cases (46.7%), and disclosed gene disruptions or CN alterations explaining clinical features in seven cases (23.3%). Even complex SVs involving numerous chromosomal segments and breakpoints were resolved efficiently, highlighting the power of combining OGM and long-read sequencing. Integrating OGM with long-read sequencing improves diagnostic resolution beyond sequencing alone and provides a robust framework for interpreting complex SVs. These findings highlight the potential clinical utility of combining OGM and long-read sequencing as a comprehensive diagnostic strategy for improved precision medicine in rare genetic diseases.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Publisher Correction: Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome. 长读技术鉴定出IQCB1中隐藏的LINE-1/ERV1插入是Senior-Løken综合征的致病变异。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-24 DOI: 10.1038/s41525-026-00559-y

Suzanne E de Bruijn, Van den Born L Ingeborgh, Ronny Derks, Lonneke Haer-Wigman, Luke O'Gorman, Frans P M Cremers, Ronald van Beek, Alexander Hoischen, Susanne Roosing, Kornelia Neveling

引用次数: 0

Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome. PTEN错构瘤综合征患者恶性和神经发育表型的基因组修饰因子。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-17 DOI: 10.1038/s41525-026-00556-1

Lamis Yehia, Lin Li, Gideon Idumah, Thomas W Frazier, Vladimir Makarov, Aritra Bose, Laxmi Parida, Antonio Hardan, Julian A Martinez-Agosto, David M Ritter, Mustafa Sahin, Charis Eng, Ying Ni

{"title":"Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome.","authors":"Lamis Yehia, Lin Li, Gideon Idumah, Thomas W Frazier, Vladimir Makarov, Aritra Bose, Laxmi Parida, Antonio Hardan, Julian A Martinez-Agosto, David M Ritter, Mustafa Sahin, Charis Eng, Ying Ni","doi":"10.1038/s41525-026-00556-1","DOIUrl":"10.1038/s41525-026-00556-1","url":null,"abstract":"PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical PTEN variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of PTEN variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (n = 171), cancer (n = 221), both phenotypes (n = 21), or neither (n = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in NDD-related genes, including DHCR7, POLG, and ARSA. Such secondary variants were less common in PTEN variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1. These findings demonstrate that PHTS phenotypes are shaped by complex gene-gene interactions beyond PTEN alone, informing mechanisms underlying the cancer-NDD dichotomy and advancing precision risk stratification.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders. 与神经发育障碍相关的新生GABBR1和GABBR2变异的功能特征

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-09 DOI: 10.1038/s41525-026-00558-z

Michal Stawarski, Noa Bielopolski, Ilana Roitman, Karen Fridman, Shane Wald-Altman, Megan Eitel, Benedict Hui, Anneke Vulto-van Silfhout, Alexander P A Stegmann, Adela Chirita-Emandi, Jacqueline Eason, Kirsty Bradshaw, Lewis Darnell, Grażyna Kostrzewa, Rafal Ploski, Romane Meurs, Amandine Batté, Stylianos E Antonarakis, Martin Gassmann, Bernhard Bettler

{"title":"Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders.","authors":"Michal Stawarski, Noa Bielopolski, Ilana Roitman, Karen Fridman, Shane Wald-Altman, Megan Eitel, Benedict Hui, Anneke Vulto-van Silfhout, Alexander P A Stegmann, Adela Chirita-Emandi, Jacqueline Eason, Kirsty Bradshaw, Lewis Darnell, Grażyna Kostrzewa, Rafal Ploski, Romane Meurs, Amandine Batté, Stylianos E Antonarakis, Martin Gassmann, Bernhard Bettler","doi":"10.1038/s41525-026-00558-z","DOIUrl":"10.1038/s41525-026-00558-z","url":null,"abstract":"GABAB receptors, the G protein-coupled receptors for the neurotransmitter GABA, are essential for regulating neuronal excitability in the brain. Monoallelic de novo missense variants in GABBR1 and GABBR2, which encode the receptor subunits, have been associated with neurodevelopmental disorders. Here, we investigated the functional impact of seven de novo missense variants in GABBR1 and GABBR2 identified in individuals with autism spectrum disorder, intellectual disability, and/or attention deficit/hyperactivity disorder. In vitro functional characterization of these variants revealed a range of gain- and loss-of-function alterations: (i) increased constitutive activity, leading to a corresponding decrease in GABA efficacy; (ii) a significant reduction in GABA potency at the receptor; and (iii) reduced surface expression, resulting in decreased GABA efficacy. While computational predictions indicated pathogenicity for all variants, our study emphasizes the importance of functional studies in clarifying the nature and scope of pharmacological changes-an essential step toward advancing targeted therapies in precision medicine.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390689","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}

引用次数: 0

Integrative analysis of in silico predictions and clinical evidence to delineate the capability of HiFi long-read sequencing in paralogous genes. 对计算机预测和临床证据进行综合分析，以描述HiFi长读测序在旁系基因中的能力。

IF 4.8 2区医学

NPJ Genomic Medicine Pub Date : 2026-03-03 DOI: 10.1038/s41525-026-00555-2

Sung Kyung Kim, Joowon Jang, Yeseul Kim, Hobin Sung, Hyesu Lee, Hara Yim, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong

{"title":"Integrative analysis of in silico predictions and clinical evidence to delineate the capability of HiFi long-read sequencing in paralogous genes.","authors":"Sung Kyung Kim, Joowon Jang, Yeseul Kim, Hobin Sung, Hyesu Lee, Hara Yim, Sung Im Cho, Jee-Soo Lee, Moon-Woo Seong","doi":"10.1038/s41525-026-00555-2","DOIUrl":"10.1038/s41525-026-00555-2","url":null,"abstract":"Paralogous genes challenge short-read sequencing (SRS) due to high sequence similarity. Although long-read sequencing (LRS) improves resolution, the extent to which it resolves paralogous genes remains unclear. This study evaluates the capability of LRS by integrating in silico mappability-based predictions with clinical data to generate SRS- and LRS-unresolved gene lists, and by assessing whether a paralog-specific phasing, Paraphase, can overcome remaining limitations. Mappability was simulated across read lengths (250 bp to 14 kb) to predict unresolved regions and validated against mapping quality (MQ) from 66 high-fidelity LRS samples. Paraphase was applied to 79 paralog groups. Among 645 medically relevant (MR) genes unresolved by SRS, 419 (65.0%) were predicted to be resolved by LRS, while 226 (35.0%) remained unresolved. These predictions correlated with clinical MQ (χ² = 92.43, p < 2.2 × 10-16; κ = 0.37), with significant differences between LRS-resolved and LRS-unresolved MR genes (W = 63,656, p < 2.2 × 10-16; r = 0.36). Paraphase resolved 61 groups (77.2%), providing additional resolution beyond LRS. LRS improves paralogous gene resolution but cannot fully eliminate paralog blind spots. Curated gene lists define boundaries of LRS utility for clinical interpretation, while Paraphase adds complementary resolution, supporting an integrated framework combining predictive modeling with algorithmic strategies.","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13076882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347748","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}

引用次数: 0