Human Mutation最新文献

{"title":"Integrated Approach to Diagnosing Limb-Girdle Muscular Dystrophies in Resource-Limited Settings","authors":"Hammad Yousaf,&nbsp;Lubaba Bintee Khalid,&nbsp;Affan Ahmed,&nbsp;Rafia Zafar Ghumman,&nbsp;Shaheer Hassan,&nbsp;Hijab Zahra,&nbsp;Ghazala Zafar,&nbsp;Kinza Rubab,&nbsp;Hazaratullah Azakai,&nbsp;Haq Nawaz Khan,&nbsp;Qamar Mahmood,&nbsp;Asmat Ali,&nbsp;Bilal Ahmad Mian,&nbsp;Zafar Ali,&nbsp;Mohammad Raza,&nbsp;Sanam Bano,&nbsp;Khairunnisa Mukhtiar,&nbsp;Uzma Abdullah,&nbsp;Shahnaz H. Ibrahim,&nbsp;Shahid M. Baig,&nbsp;Mathias Toft,&nbsp;Salman Kirmani,&nbsp;Zafar Iqbal,&nbsp;Ambrin Fatima","doi":"10.1155/humu/1321391","DOIUrl":"10.1155/humu/1321391","url":null,"abstract":"<p>Limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of neuromuscular disorders characterized by overlapping clinical features, including progressive muscle weakness and wasting, elevated creatine kinase (CK) levels, and motor and skeletal abnormalities. Due to phenotypic overlap and variable severity, clinical diagnosis alone is often unreliable. Incorporation of genetic investigations to aid diagnosis/differential diagnosis has accelerated the diagnostic process but remains largely limited to developed countries. Here, we employed genetic testing as a first-tier approach to simplify the diagnostic journey in a resource-limited setting, combined with preliminary functional analyses to identify the underlying genetic cause. Our cohort included 46 affected individuals (31 males, 15 females) from 29 families with a mean age of 23.59 ± 11.87 years and a mean age at onset of 14.8 ± 9.2 years. All individuals presented with progressive muscle weakness, elevated CK levels, movement difficulties, and gait abnormalities. Genetic testing identified pathogenic/likely pathogenic variants in <i>CAPN3</i> (8 families)<i>, DYSF</i> (15 families), <i>LAMA2</i> (4 families), and <i>SGCA</i> (1 family), whereas a variant of uncertain significance was identified in <i>COL12A1</i> (1 family). Preliminary functional investigations in patient-derived fibroblasts demonstrated that the COL12A1: p.(Val1051Leu) identified in Family 1 results in reduced mRNA and protein abundance. Overall, 25 unique variants were identified, including 17 novel variants. This study highlights the utility of integrating genetic and functional approaches to facilitate accurate diagnosis in low- and middle-income settings.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108817","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":"Genotype–Phenotype Relationships in Patients Carrying Biallelic FDXR Pathogenic Variants—New Cases and Systematic Review","authors":"Antoine Paul,&nbsp;Ghizlene Lahlou,&nbsp;Sophie Achard,&nbsp;Jérôme Nevoux,&nbsp;Isabelle Mosnier,&nbsp;Isabelle Rouillon,&nbsp;Yann Nguyen,&nbsp;Maya Benali,&nbsp;Jean-François Papon,&nbsp;Agnes Rotig,&nbsp;Margaux Serey-Gaut,&nbsp;Celine Labeyrie,&nbsp;Guillemette Beaudonnet,&nbsp;Laurence Jonard,&nbsp;Ralyath Balogoun,&nbsp;Sandrine Marlin","doi":"10.1155/humu/5928629","DOIUrl":"10.1155/humu/5928629","url":null,"abstract":"<p>Biallelic pathogenic <i>FDXR</i> variations were identified in 2017 as being responsible for sensorial neuropathies. The first reported patients suffered from auditory and optic sensorineural impairments (ANOA, MIM #617717). Since then, many publications have described various phenotypes including peripheral and central nervous systems impairments (MMDS9B, MIM #620887). This is consistent with the role of the encoded protein ferredoxin reductase (FDXR) as one of the actors of iron-sulfur proteins synthesis in mitochondria. Ophthalmologic and neurologic symptoms have often been reported, but little is known about the associated inner ear disabilities, although hearing loss was described in the early clinical reports. Firstly, we would like to characterize inner ear abnormalities, sharing our observations of five new patients′ hearing and the outcome after rehabilitation. Thereafter, considering the increasing numbers of publications about <i>FDXR</i>, it appeared useful to provide an overview of literature, analyzing how molecular data may correlate with clinical symptoms. We analyzed the clinical and molecular findings in patients reported from 2017 until March 2025. Data included 89 cases from 79 unrelated families. Protein changes were mostly located in the FAD binding domain, whereas those in NADPH binding domains seem to be less prevalent but more related to severe cases with earlier onset symptoms. These data, combined with current knowledge about FDXR catalytic function and its interaction with FDX and/or cytochrome P450 proteins, could help to understand potential phenotype-genotype correlations.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108902","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":"Novel Strategy for Structural Variant Genotyping by Short-Read Genomic Sequencing From Restriction-Circles: Experimental and Bioinformatics Proof-of-Concept","authors":"Miguel M. Abelleyro,&nbsp;Patricio Yankilevich,&nbsp;Betiana M. Ziegler,&nbsp;Leonela Luce,&nbsp;Héctor M. Cifuentes,&nbsp;Claudia P. Radic,&nbsp;Liliana C. Rossetti,&nbsp;Florencia Giliberto,&nbsp;Carlos D. De Brasi","doi":"10.1155/humu/2169350","DOIUrl":"10.1155/humu/2169350","url":null,"abstract":"<p>Structural variants (SVs) comprise copy-number variants (e.g., deletions and duplications) and copy-neutral SV (e.g., perfect inversions). Short-read high-throughput DNA-sequencing is the established technology for small-variant calling in clinical genomics, whereas Oxford nanopore or PacBio long-read NGS technologies improve SV identification but remain challenging to implement in clinical settings. We developed and validated a novel experimental protocol and bioinformatics pipeline for SV genotyping from short-read whole-genome sequencing (WGS) of restriction-circles of DNA. The experimental protocol includes <i>Bcl</i>I-restriction digestion of genomic DNA, fragment-ends ligation and short-read WGS. The bioinformatics pipeline takes advantage of linking pair-end reads (LPERs), a key operator associating terminal sequences from each restriction fragment. LPERs contain long-distance haplotype information, essential for SV-genotyping. Each SV associates with a specific LPER pattern. The approach was applied to a patient with Duchenne muscular dystrophy (DMD) generating proper LPER vertical (8.6x) and horizontal (83%) coverages with good quality standards. SV-specific LPER quality filters were designed to improve the consistency of SV detection. The approach was validated by verifying a previously characterised <i>DMD</i>-genotype in the proband (<i>DMD</i>_exons_45-54 deletion and <i>DMD</i>_exons_38-43 duplication) with our output. Conventional SV genotyping using other SV detection algorithms can still be successfully applied to complete an accurate definition of the rearrangement. Our SV-genotyping algorithm detected two novel SVs in Xq28, which were verified by direct molecular investigation, and resulted polymorphic in the general population: a 1.4 kb deletion, allelic frequency AF (CI95%) of 0.83 (0.71–0.91) and a perfect inversion with 0.31 (0.08–0.54) originated by recombination of 99% homologous 8.4 kb inverted repeats (IRs). Although IR-mediated inversions represent a major challenge for WGS-based genotyping, our approach correctly indicated the absence of haemophilia recurrent inversions. Additionally, our protocol allows application of regular small-variant calling. A likely benign SNV in <i>F8</i>-intron-3 was also identified and verified. The potential clinical utility of this approach is supported by its consistency and ability to improve SV genotyping whilst allowing the application of conventional variant calling algorithms.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108038","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":"A De Novo Arg649Trp Variant in GluA2 Impairs Its Assembly With GluA1: Associated With Epilepsy and Neurodevelopmental Disorders","authors":"Jing-Wen Chen,&nbsp;Ying-Chun Lin,&nbsp;Ping Hu,&nbsp;Feng-Chang Qiao,&nbsp;Yan Wang,&nbsp;Qing-Qing Li,&nbsp;Shi-Ji Deng,&nbsp;Qin-Xin Zhang,&nbsp;Jiang Chen,&nbsp;Yun Stone Shi","doi":"10.1155/humu/3227151","DOIUrl":"10.1155/humu/3227151","url":null,"abstract":"<p>AMPA-type glutamate receptors (AMPARs) are the main mediators for fast excitatory synaptic transmission in the brain. Among AMPAR subunits, GluA2 is unique because of its role in forming Ca²⁺-impermeable heteromeric receptors with GluA1/A3/A4, a property dictated by an arginine residue (GluA2(R)) in the pore region. In contrast, GluA2(R)-lacking AMPARs are Ca²⁺-permeable. Through whole-exome sequencing (WES), we identified a de novo <i>GRIA2</i> variant (c.1945A&gt;T, p.Arg649Trp) in a patient with neurodevelopmental disorders (NDDs) and epilepsy. Heterologous expression in HEK293T cells revealed that homomeric GluA2(Q)_Arg649Trp and heteromeric GluA1/A2(R)_Arg649Trp receptors retained near-normal gating kinetics compared to wild-type (WT). However, rectification index (RI) analysis demonstrated impaired assembly of GluA2(R)_Arg649Trp with GluA1. At 1:1 or 1:2 expression ratio (GluA1:GluA2), the Arg649Trp mutant exhibited a lower RI than WT, accompanied by reduced surface expression when coexpressed with GluA1. These results suggest that the Arg649Trp variant compromises the ability of GluA2 to incorporate into heteromeric AMPARs, leading to an increased proportion of GluA1 homomeric/Ca²⁺-permeable receptors. Notably, recurrent missense variants at the M3–S2 linker of GluA2, including Ala639Ser and Thr646Asn, have also been independently identified to impair AMPAR assembly, suggesting this could be a common pathological mechanism. We thus propose that altered subunit stoichiometry, rather than changes in channel gating kinetics, represents a primary pathogenic mechanism for this <i>GRIA2</i> variant, contributing to NDD pathogenesis by elevating Ca²⁺-permeable AMPARs in the brain.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108819","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":"Genetic Analysis and Reproductive Intervention in a Duchenne Muscular Dystrophy Family With Cryptic Complex Chromosomal Rearrangement Identified by Structural Variation Sequencing","authors":"Shengfang Qin,&nbsp;Xueyan Wang,&nbsp;Jin Wang,&nbsp;Xiangyou Leng,&nbsp;Zhuo Zhang,&nbsp;Ximin Chen,&nbsp;Yan Yin","doi":"10.1155/humu/8333541","DOIUrl":"10.1155/humu/8333541","url":null,"abstract":"<p>Duchenne/Becker muscular dystrophy (DMD/BMD) is caused by variants in the X-linked <i>DMD</i> gene—most commonly deletions, duplications, or point mutations, and only rarely by complex chromosomal rearrangements (CCRs). In this study, structural variant sequencing (SVseq) was applied to a 14-year-old male patient with DMD. Although the patient exhibited typical symptoms, conventional tests—including karyotype analysis, gene panel, whole-exome sequencing (WES), and multiplex ligation–dependent probe amplification (MLPA)—were all negative. SVseq identified a novel complex rearrangement on the X chromosome, comprising a 974,456 bp inversion spanning the 5 ^′ UTR and Exons 1–2 of the <i>DMD</i> gene, flanked by two microdeletions of 7285 and 6468 bp (NC_000023.11:g.[32865334_32872619del;32872619_33847075inv33847075_33853543del]). This rearrangement disrupts the <i>DMD</i> coding sequence and is classified as a pathogenic variant. Short tandem repeat (STR) analysis confirmed the familial relationship, whereas PCR and Sanger sequencing precisely mapped the breakpoints, establishing that the mutation arose de novo in his mother and was maternally inherited. Reproductive interventions—including preimplantation genetic testing for monogenic disorders (PGT-M) and second-trimester prenatal diagnosis—enabled the successful birth of a healthy male child. SVseq demonstrated clear advantages over standard methods for detecting CCRs, highlighting its value in genetically elusive cases. We recommend SVseq as a complementary diagnostic tool for unresolved DMD cases where conventional testing does not explain the findings. This approach can enhance diagnostic yield and support informed family planning.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108889","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":"Expanding the Molecular Data of DICER1-Related Tumor Predisposition: Novel Germline Variants in an Argentine Pediatric Cohort","authors":"Sofía Trobo,&nbsp;Natalia Pérez Garrido,&nbsp;Pablo Ramírez,&nbsp;Fiorella Tesan,&nbsp;Elisa Vaiani,&nbsp;Noelia Dujovne,&nbsp;Natalia Gazek,&nbsp;Jessica Lopez Martí,&nbsp;Mariana Lavia,&nbsp;Guido Felizzia,&nbsp;Victoria Pringles,&nbsp;Melisa Agotegaray,&nbsp;Nora Saraco,&nbsp;Marta Ciaccio,&nbsp;Alicia Belgorosky,&nbsp;Roxana Marino","doi":"10.1155/humu/3621830","DOIUrl":"10.1155/humu/3621830","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background/Objective</h3>\u0000 \u0000 <p><i>DICER1</i>-related tumor predisposition is a rare hereditary tumor predisposition disorder characterized by autosomal dominant inheritance, reduced penetrance, and variable expressivity. This study is aimed at describing the clinical and molecular spectrum of <i>DICER1</i>-related tumor predisposition in an Argentine pediatric cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Design and Methods</h3>\u0000 \u0000 <p>Seventeen unrelated patients with <i>DICER1</i>-related tumor predisposition and 54 relatives were evaluated at “Prof. Dr. J. P. Garrahan” Pediatric Hospital (Buenos Aires, Argentina) between 2014 and 2024. Germline and somatic <i>DICER1</i> variants were analyzed using Sanger or next-generation sequencing. Functional assays were performed for selected intronic variants. Three samples of poorly differentiated thyroid carcinoma were also included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Sixteen distinct germline variants were identified in the 17 index cases, including 12 novel alterations (75%). One quarter of the variants were de novo. Thyroid involvement, particularly multinodular goiter and papillary thyroid carcinoma, was the most common presentation and frequently coexisted with ovarian Sertoli–Leydig cell tumors or embryonal rhabdomyosarcoma. Two novel intronic variants were confirmed to affect splicing by RT-PCR. Somatic “hotspot” mutations in exons 24–25 (RNase IIIb domain) were detected in most tumors, consistent with the two-hit model. The identification of asymptomatic carriers enabled early surveillance and preventive interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study expands the molecular spectrum of germline <i>DICER1</i> variants, reinforces the predominance of thyroid involvement, and highlights the value of molecular testing for diagnosis, genetic counseling, and early intervention. Ethical considerations regarding surveillance and management of asymptomatic carriers remain an important area in need of future guidance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108821","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":"Zinc Transporter Gene Variants (SLC30A and SLC39A) in Human Disease: From Metal Homeostasis Disruption to Convergent Signaling Pathways","authors":"Bo Sun,&nbsp;Jing Ma,&nbsp;Xiaohong Bai,&nbsp;Shusong Wang","doi":"10.1155/humu/8829745","DOIUrl":"10.1155/humu/8829745","url":null,"abstract":"<p>Zinc, an indispensable trace element, performs critical functions in human physiology. As a versatile cofactor, zinc participates in over 1000 enzymatic reactions and regulates more than 2000 transcription factors, orchestrating diverse cellular signaling pathways. The transmembrane transport of zinc is mediated by specialized transporter proteins, which are categorized into two families: zinc transporters (ZnTs) and Zrt- and Irt-like proteins (ZIPs). These transporters are pivotal for maintaining cellular and systemic zinc homeostasis. Pathogenic variants in ZnT/ZIP genes are associated with a spectrum of severe human diseases. This review systematically examines the pathophysiological connections between ZnT/ZIP gene variants and human diseases, providing a conceptual framework for future mechanistic investigations.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080484","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":"Knowledge Mapping of Human Genetic Variation in Multiomics Biomarker Translation: A Bibliometric Analysis","authors":"Bangshu Zhao,&nbsp;Wei Ran,&nbsp;Ning Liang","doi":"10.1155/humu/5730260","DOIUrl":"10.1155/humu/5730260","url":null,"abstract":"<p>Human genetic variation and multiomics biomarker translation has emerged as a rapidly developing research field at the intersection of molecular medicine, bioinformatics, and clinical decision-making. This study used bibliometric methods to map its global structure, intellectual base, and thematic evolution. The eligibility framework was deliberately restricted to studies in which inherited or somatic human genetic variation was substantively linked to omics-integrated biomarker discovery, functional interpretation, clinical stratification, or therapeutic response; generic omics studies without a variation-linked translational endpoint were excluded. Publications indexed in Scopus, Web of Science, and PubMed from 2003 to 2025 were retrieved, screened, converted into Web of Science format, and analyzed using CiteSpace, VOSviewer, and the R package bibliometrix. A total of 673 publications were included. The annual output showed sustained acceleration, indicating a transition from exploratory molecular association studies to a more mature translational framework. Research activity was concentrated in a limited number of countries and institutions, led by the United States, with China contributing substantial output but lower citation impact relative to publication volume. The institutional network was dominated by large academic medical centers, national research systems, and oncology-oriented consortia, reflecting the infrastructural demands of biomarker translation. Journal analysis showed a dual structure in which specialized translational and omics journals accounted for much of the current output, whereas the intellectual foundations remained anchored in high-impact journals in genetics, oncology, and clinical medicine. Keyword and overlay analyses revealed a clear thematic shift from pharmacogenetics and single-marker discovery toward genomics-guided, multiomics-integrated, and clinically actionable biomarker models, with recent emphasis on liquid biopsy, heterogeneity, artificial intelligence, machine learning, and the tumor microenvironment. At the variant level, the major translational bottleneck is increasingly the functional connection between DNA-level variation and downstream RNA, protein, pathway, and clinical phenotypes rather than variant detection alone. The literature is therefore increasingly oriented toward externally validated and computationally interpretable biomarker systems, whereas routine clinical implementation remains constrained by functional validation, assay standardization, prospective evaluation, and regulatory requirements.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074516","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":"Genotype and Phenotype of 198 Korean Patients With Nonlethal Osteogenesis Imperfecta: A Retrospective Cohort Study","authors":"Junpyo Lee,&nbsp;Hye Ran Lee,&nbsp;Jung Min Ko,&nbsp;Chang Ho Shin,&nbsp;Wonik Lee,&nbsp;Mi Hyun Song,&nbsp;Tae-Joon Cho","doi":"10.1155/humu/5521427","DOIUrl":"10.1155/humu/5521427","url":null,"abstract":"<p>Osteogenesis imperfecta (OI) is a heterogeneous group of genetic skeletal disorders characterized by bone fragility and low bone mass, manifesting as multiple fractures and deformities of the spine and extremities. Although genotype-phenotype correlations have been studied in various populations, large-scale data in Koreans have been lacking. This study is aimed at characterizing the clinical and genetic spectrum of nonlethal OI in the Korean population and explore genotype–phenotype associations. This retrospective cohort study analyzed 198 genetically confirmed Korean OI probands evaluated at a single center between 2004 and 2024, with clinical features reviewed and genetic testing performed using Sanger sequencing and targeted next-generation sequencing. A total of 160 distinct pathogenic variants were identified, including 44 novel variants. Variant pathogenicity was assessed according to the ACMG/AMP variant classification guidelines. Pathogenic variants of <i>COL1A1</i> and <i>COL1A2</i> accounted for 87.4% of cases, with <i>COL1A1</i> variants being the most prevalent (66.7%). Only 4.0% of cases had autosomal recessive OI. Glycine substitution (GS) variants were associated with significantly more severe phenotypes than other variants, including shorter height (median z-score−3.67 [IQR −8.37 to −1.78] vs. −1.17 [−1.96 to −0.16], <i>p</i> &lt; 0.001) and earlier fracture onset (1.00 [0.00–8.25] vs. 15.00 [7.00–24.75] months, <i>p</i> &lt; 0.001). In <i>COL1A1</i>, GS variants closer to the C-terminus correlated with significantly more severe height reduction (Spearman <i>ρ</i> = −0.478, <i>p</i> = 0.005). The genotype–phenotype analysis confirmed the phenotypic severity of GS, particularly for variants closer to the C-terminus of <i>COL1A1</i>, consistent with previous studies. Additionally, the identification of 44 novel variants expands the variant spectrum of OI. These findings provide valuable insights into genetic diagnosis, prognostic assessment, and clinical management of OI.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074470","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":"Pathogenic LRSAM1 RING Domain Variants Disrupt Intracellular Protein Localization in Charcot–Marie–Tooth Disease Type 2P","authors":"Johanna E. Hakonen,&nbsp;Tom P. Hellings,&nbsp;Esther Dingemanse,&nbsp;Bo Laman,&nbsp;Olaf J. Froncek,&nbsp; NynkeWienholts,&nbsp;Naima Lamzira-Arichi,&nbsp;Marlene van den Berg,&nbsp;Frank Baas,&nbsp;Noam Zelcer,&nbsp;Marian A. J. Weterman","doi":"10.1155/humu/7169970","DOIUrl":"https://doi.org/10.1155/humu/7169970","url":null,"abstract":"<p>Charcot–Marie–Tooth Disease Type 2P (CMT2P) is an inherited axonal neuropathy caused by dominant mutations in the RING domain of LRSAM1. The precise cellular consequences of these mutations remain unclear. Here, we investigated the subcellular localization of wild-type and RING mutant LRSAM1 in multiple cell models, including patient-derived fibroblasts and neuronal cell lines. Using immunocytochemistry, membrane and lipid droplet fractionation, and colocalization with organelle markers, we found that RING mutant LRSAM1 consistently mislocalized, deviating from its typical diffuse cytosolic pattern to form large perinuclear aggregates. This mislocalization also caused abnormal clustering of the LRSAM1 target protein TSG101 that coaggregated with mutant LRSAM1. Wild-type LRSAM1 predominantly localized to the cytosolic fraction, whereas the mutant protein shifted toward the membranous fraction. Wild-type LRSAM1 was also observed in the lipid droplet fraction, whereas mutant LRSAM1 was absent. Our findings demonstrate that pathogenic RING mutations in LRSAM1 disrupt its subcellular localization and that of its targets. These results highlight protein mislocalization as a pathogenic mechanism in CMT2P, providing new insight into disease etiology.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7169970","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048131","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}