Human Mutation最新文献

{"title":"Clinical and Genetic Spectrum of Large AIP Deletions","authors":"Tea Shehu Kolnikaj,&nbsp;Maren Ruka,&nbsp;Artur Xhumari,&nbsp;Anila Babameto-Laku,&nbsp;Athanasios Siolos,&nbsp;Panagiotis Alexandros Drakos,&nbsp;Kesson Magid,&nbsp;Thomas O. Millner,&nbsp;Robert D. Murray,&nbsp;Marinella Tzanela,&nbsp;Dragana Miljić,&nbsp;Arlinda Ramaj,&nbsp;Paul Benjamin Loughrey,&nbsp;Stelios Tigas,&nbsp;Márta Korbonits","doi":"10.1155/humu/4212742","DOIUrl":"https://doi.org/10.1155/humu/4212742","url":null,"abstract":"<p>Familial isolated pituitary adenoma (FIPA) accounts for approximately 2%–5% of all pituitary adenomas, with inactivating variants of the aryl hydrocarbon receptor-interacting protein (<i>AIP</i>) gene representing the most frequent known genetic cause. Clinically, patients with <i>AIP</i> variants often have young-onset macroadenomas with growth hormone hypersecretion, although disease severity and penetrance are variable. Most reported <i>AIP</i> variants are point mutations, whereas large deletions are rare and potentially underdiagnosed. Accurate detection of <i>AIP</i> copy-number variants requires methods such as multiplex ligation-dependent probe amplification or validated copy-number analysis of next-generation sequencing data, as Sanger sequencing alone may fail to identify these alterations. Due to the rarity of the disease, it is unknown whether large deletions in the ubiquitously expressed <i>AIP</i> gene are associated with potentially more severe phenotype. Available data suggest that large deletions may occur in 8%–10% of <i>AIP</i> mutation-positive pedigrees, highlighting the importance of incorporating copy-number variant detection into <i>AIP</i> testing workflows. We analysed data from all published patients with large <i>AIP</i> deletions (<i>n</i> = 25) and report here two novel large <i>AIP</i> deletions (Exons 3–4 and Exons 2–6 deletions) and three additional three families, including an Albanian kindred associated with metastatic Hürthle cell thyroid carcinoma. No major differences compared with other <i>AIP</i> variants were found in age at diagnosis, tumour size, hormonal profile, sex distribution or presence of other tumours. A role for <i>AIP</i> variants in thyroid carcinogenesis is unlikely.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4212742","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943296","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 Novel Technique for Validating Copy Number Variants and Its Application in Familial Exudative Vitreoretinopathy","authors":"Li-li Zhang,&nbsp;Zi-jia Zhao,&nbsp;Kai-xin Chen,&nbsp;Yu-qiao Ju,&nbsp;Feng-juan Gao,&nbsp;Yuan Zong,&nbsp;Qing Chang,&nbsp;Xin Huang,&nbsp;Ting Zhang,&nbsp;Ge-zhi Xu","doi":"10.1155/humu/9556416","DOIUrl":"https://doi.org/10.1155/humu/9556416","url":null,"abstract":"<p>Inherited diseases have a strong genetic basis, with copy number variants (CNVs) playing a crucial role in their pathogenesis. However, the detection and validation of CNVs remain challenging. In this study, we introduce target enrichment polymerase chain reaction (tecPCR), a novel technique that integrates multiplex polymerase chain reaction (PCR) with next-generation sequencing (NGS) for enhanced CNV validation, and applied it in familial exudative vitreoretinopathy (FEVR). Using NGS, 97 variants linked to FEVR were identified, including 91 SNVs and 6 CNVs. Of the CNVs, 66.67% (4/6) were validated both by quantitative PCR and tecPCR, yielding a positive predictive value of 100% (95% confidence intervals: 39.8%–100%) and negative predictive value of 100% (95% confidence intervals: 15.8%–100%) for tecPCR in this pilot validation. The validated FEVR genetic test showed a positivity rate of 53.07% (95/179). Moreover, the demographic and ocular features of the FEVR patients with CNVs were comparable to those with SNVs. This study broadens the mutation spectrum of FEVR and demonstrates that tecPCR provides exceptional specificity and sensitivity, making it a promising tool for genetic diagnostics.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9556416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943294","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":"Identification of COPZ1 as a Shared Candidate Ferroptosis-Related Hub Gene in Periodontitis and Inflammatory Bowel Disease","authors":"Xin Yu,&nbsp;Yun Ruan,&nbsp;Zongying Zhang,&nbsp;Jiyuan Shi,&nbsp;Xinyu Gu,&nbsp;Yuyi Chen,&nbsp;Mengmeng Sang,&nbsp;Xiaorong Zhou,&nbsp;Yan Zhou,&nbsp;Liming Mao","doi":"10.1155/humu/6316527","DOIUrl":"https://doi.org/10.1155/humu/6316527","url":null,"abstract":"<p>Clinical and epidemiological evidence demonstrates a robust bidirectional link between inflammatory bowel disease (IBD) and periodontitis, with IBD patients having a significantly elevated risk of periodontitis. Although this association is well established, the shared molecular mechanisms remain unclear. Both IBD, including Crohn′s disease (CD) and ulcerative colitis (UC), and periodontitis feature aberrant ferroptosis activation, which drives oxidative damage and tissue breakdown. We therefore hypothesized that ferroptosis is a core pathogenic mechanism common to all three conditions. Using GEO transcriptomic data, we identified 116, 134, and 255 exploratory candidate ferroptosis-related differentially expressed genes in CD, UC, and periodontitis, respectively, with 55 candidate genes overlapping across all three conditions. Four machine learning–based feature selection algorithms consistently ranked COPZ1 as the top hub gene. In animal models of colitis and periodontitis, COPZ1 showed markedly elevated protein levels in inflamed intestinal and gingival tissues. In vitro experiments demonstrated that COPZ1 knockdown upregulated the expression of ferroptosis-inhibitory genes (Gpx4, Slc7a11, and Fth1) in RAW264.7-ASC macrophages under both basal and LPS-induced inflammatory conditions, and reversed LPS-mediated downregulation of Gpx4, suggesting that COPZ1 is involved in the regulation of ferroptosis in macrophages. Immune infiltration analysis revealed correlations between COPZ1 expression and the abundance of macrophages, neutrophils, B cell subsets, and T cell subsets, suggesting its association with differences in estimated immune cell composition. Single-cell RNA sequencing from CD patient biopsies further demonstrated heterogeneous COPZ1 expression across diverse intestinal immune cell types (including neutrophils, CD8⁺ T cells, CD4⁺ T cells, and macrophages) and linked to ferroptosis-associated intercellular signaling. In silico drug prediction identified nine small-molecule compounds that stably bound to COPZ1 through hydrogen bonds. Molecular dynamics simulations subsequently ranked BRD-K66453893 as the compound exhibiting the greatest structural stability among the tested candidates. Collectively, our findings identify COPZ1 as a shared candidate ferroptosis-related hub gene for CD, UC, and periodontitis, and highlight its association with the inflammatory immune microenvironment, thereby providing a promising therapeutic target for these interrelated chronic inflammatory disorders.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6316527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943549","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":"The Charcot–Marie–Tooth Neuropathy (CMTX3) Complex Structural Variation Causes Differential SOX3 Spatiotemporal Expression","authors":"Alexandra Boyling,&nbsp;Anthony N. Cutrupi,&nbsp;Desmond Li,&nbsp;Ben Crossett,&nbsp;Jonathan J. Danon,&nbsp;Edward D. Harvey-Latham,&nbsp;Garth A. Nicholson,&nbsp;Steve Vucic,&nbsp;Marina L. Kennerson","doi":"10.1155/humu/4225263","DOIUrl":"https://doi.org/10.1155/humu/4225263","url":null,"abstract":"<p>Charcot–Marie–Tooth (CMT) neuropathy is a clinically and genetically heterogeneous group of diseases characterized by the length-dependent axonal degeneration of peripheral nerves. We previously mapped a rare form of X-linked CMT, CMTX3, to a 5.7-Mb interval on chromosome Xq26.3-q27.1 and excluded the coding region of all known genes in the linkage interval for mutations. Whole genome sequencing subsequently identified a 78-kb region of chromosome 8q24.3 that had been duplicated and inserted into the CMTX3 locus between the genes <i>HAPSTR2</i> and <i>SOX3</i>. The 78-kb insertion, which contains a partial transcript of <i>ARHGAP39</i>, fully segregated in families with CMTX3 and was absent in neurologically normal controls. To retain the CMTX3 insertion and investigate its consequences in appropriate neuronal tissue, we generated induced pluripotent stem cells (iPSCs) from CMTX3 fibroblasts. Using bulk RNA sequencing of patient-derived spinal motor neurons, <i>ARHGAP39</i> was deemed nonpathogenic by excluding both the formation of novel fusion transcripts and dosage effects from the partial duplication. Subsequent NanoString expression analyses of candidate genes within the CMTX3 locus, across different stages of neuronal differentiation, identified spatiotemporal dysregulation of <i>SOX3.</i> NanoString showed reduced <i>SOX3</i> expression in patient iPSCs. RNA sequencing detected <i>SOX3</i> downregulation in CMTX3 neuroepithelial progenitor cells, which was further confirmed by quantitative proteomics. Given the early onset and relatively rapid progression of CMTX3, these data prioritise <i>SOX3</i> as a leading candidate gene, consistent with its role as one of the earliest transcription factors expressed in the developing nervous system and a key regulator of neuronal fate.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4225263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943082","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":"Comment on “Obituary: Professor Andreas Gal”","authors":"Christian Kubisch,&nbsp;Kerstin Kutsche","doi":"10.1155/humu/8991628","DOIUrl":"https://doi.org/10.1155/humu/8991628","url":null,"abstract":"&lt;p&gt;It is with great sadness that we announce the passing of Professor Andreas Gal, who died on May 20, 2026. He served as an editor of &lt;i&gt;Human Mutation&lt;/i&gt;; his editorial work was distinguished by integrity, fairness, and an unwavering commitment to supporting researchers from around the world.&lt;/p&gt;&lt;p&gt;Andreas Gal was born on September 18, 1947, in Debrecen, Hungary. He studied medicine at the University of Szeged from 1966 to 1972 before beginning his scientific career at the prestigious Institute of Genetics of the Hungarian Academy of Sciences in Szeged, where he worked from 1973 to 1983. Following a brief appointment at the Institute of Human Genetics in Freiburg, Germany, he became head of the Laboratory of Molecular Human Genetics and DNA Diagnostics at the Institute of Human Genetics, University of Bonn, in 1985. In this role, he emerged as one of the pioneers of molecular genetics diagnostics in Germany. In 1990, together with his appointment to a professorship funded by the Schilling Foundation, he became head of the Research Group for Molecular Human Genetics and DNA Diagnostics at the Institute of Human Genetics, Medical University of Lübeck, Germany. In 1994, he was appointed full professor and director of the Institute of Human Genetics at the University Medical Center Hamburg-Eppendorf, Hamburg, Germany.&lt;/p&gt;&lt;p&gt;Andreas Gal is particularly renowned for his contributions to the identification of disease-causing genes and the elucidation of molecular mechanisms underlying both rare and more common inherited disorders. His research encompassed a broad spectrum of genetic diseases, including retinitis pigmentosa, Norrie disease [&lt;span&gt;1&lt;/span&gt;], Usher syndrome, and systemic lysosomal disorders such as the mucopolysaccharidoses [&lt;span&gt;2&lt;/span&gt;–&lt;span&gt;4&lt;/span&gt;] and Fabry disease [&lt;span&gt;5&lt;/span&gt;]. Among his most influential publications are seminal studies on the genetic basis of &lt;i&gt;RPE65&lt;/i&gt;-associated Leber congenital amaurosis [&lt;span&gt;6&lt;/span&gt;], &lt;i&gt;RDH12&lt;/i&gt;-associated retinal dystrophy [&lt;span&gt;7&lt;/span&gt;], retinitis pigmentosa, &lt;i&gt;MERTK&lt;/i&gt;-associated retinal disease [&lt;span&gt;8&lt;/span&gt;], &lt;i&gt;CDH23&lt;/i&gt;-associated Usher syndrome [&lt;span&gt;9&lt;/span&gt;], and autosomal recessive posterior microphthalmia caused by pathogenic variants in &lt;i&gt;PRSS56&lt;/i&gt; [&lt;span&gt;10&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In recognition of his outstanding scientific achievements, Andreas Gal received numerous prestigious awards. These included the “Fight Against Blindness” research award from the German and Swiss Retinitis Pigmentosa Associations in 1989; the recognition award from the Alcon Research Institute (Fort Worth, Texas) in 2006 for outstanding contributions to vision research; the recognition award from Retina International in 2012 for exceptional achievements in the field; and, in 2013, the Honorary Medal of the German Society of Human Genetics in recognition of his distinguished contributions to human genetics. In 2017, he delivered the prestigious François Lecture at the meeting of the Interna","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8991628","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943306","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":"First Cornelia de Lange Syndrome Type 4 Caused by the Gonadal Mosaicism of RAD21 Deletion","authors":"Yanchuan Xie,&nbsp;Dongyan Li,&nbsp;Wensheng Li,&nbsp;Yingjie Tao,&nbsp;Li Tang,&nbsp;Liping Li,&nbsp;Guangda Li,&nbsp;Hongwei Jiang","doi":"10.1155/humu/5591607","DOIUrl":"10.1155/humu/5591607","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cornelia de Lange syndrome (CdLS) currently has seven known causative genes, inherited in an autosomal or X-linked dominant pattern. Clinical features are variable, including dysmorphic facial features, intrauterine and/or postnatal growth retardation, multiple organ system malformations, and neurodevelopmental disorders. Type 4 of CdLS caused by <i>RAD21</i> gene has a relatively mild phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we report a pair of siblings from a Chinese family who both have similar dysmorphic facial features, cleft palate, spina bifida occulta, and limb phenotypes. Whole-genome sequencing (WGS) was performed to analyze the genetic basis of their condition. Gap-PCR was subsequently employed to map the breakpoints in the affected siblings′ peripheral blood samples. Additionally, the copy number status of the parents and the father′s sperm DNA were evaluated using Gap-PCR and digital PCR (dPCR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through WGS analysis, a heterozygous deletion was found in the 8q23.3-8q24.11 region of both patients, which includes the full-length <i>RAD21</i> gene. And we mapped the breakpoint with the peripheral blood samples of the affected siblings using Gap-PCR. The parents′ peripheral blood had normal copy number. The father′s sperm DNA was negative for the deletion by both Gap-PCR and dPCR, whereas the mother′s peripheral blood was also negative, suggesting the deletion is likely due to maternal gonadal mosaicism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We report a pair of siblings with a complete loss of <i>RAD21</i>, with evidence supporting maternal gonadal mosaicism. This information will be helpful for genetic counseling for Type 4 of CdLS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919834","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":"Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants","authors":"Yonatan Amzaleg,&nbsp;Kevin J. McDonnell,&nbsp;Gregory E. Idos,&nbsp;Christina Mathai,&nbsp;Stacy W. Gray,&nbsp;Heather Hampel,&nbsp;David W. Craig","doi":"10.1155/humu/7456837","DOIUrl":"10.1155/humu/7456837","url":null,"abstract":"<p>Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair–deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ −0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919814","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":"TRACE: A Framework for Integrating Transcript Relevance Into ACMG/AMP Variant Interpretation","authors":"Himanshu Goel","doi":"10.1155/humu/1095011","DOIUrl":"10.1155/humu/1095011","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Accurate clinical variant interpretation depends on the transcript used for annotation and consequence assessment. Transcript-aware reasoning is also incorporated into existing ClinGen guidance for loss-of-function, splicing, functional and computational evidence and into gene- and disease-specific specification. However, limited guidance exists when unresolved transcript context warrants escalation beyond routine annotation, how heterogeneous transcript-relevance evidence should be integrated or how the resulting determination should be documented.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We propose TRACE (Transcript Relevance Assessment for Clinical Evaluation), a four-tiered gated framework. Applicable gene- or disease-specific Variant Curation Expert Panel (VCEP) specifications take precedence where they resolve the transcript question. Otherwise, TRACE begins with standard transcript annotation, escalates to focused transcript-relevance assessment only when transcript context could materially alter molecular consequence or criterion applicability and reserves targeted developmental, RNA, protein or functional evidence for unresolved cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TRACE separates transcript-context assessment from criterion-specific evidence assignment. Transcript context may establish whether the biological prerequisite for PVS1, PM1, PM4, PS3/BS3 or PP3/BP4 assessment is satisfied; established ClinGen SVI or gene-specific guidance then determines whether the criterion is applied and at what strength. Representative mechanisms include exon utilisation in <i>TTN</i>, poison-exon regulation in <i>SCN1A</i>, promoter-specific isoforms in <i>DMD</i> and regulatory transcript architecture in <i>FKRP</i>. A <i>YAP1</i> example demonstrates withholding PVS1 when an alternative transcript preserves a downstream product, whereas <i>CDKL5</i> illustrates a historical diagnosis missed through transcript selection and now governed by gene-specific expert curation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>TRACE is an escalation and documentation framework, not a parallel evidence-weighting system. Its primary aim is to make clinically material transcript determinations explicit, reproducible and auditable while preserving established SVI/VCEP rules for evidence application and strength. Whether TRACE improves classification accuracy, interlaboratory concordance or diagnostic yield requires empirical validation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905657","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":"The Role of Genetic Variation in Phenotypic Variability in Loeys–Dietz Syndrome","authors":"Hussein Abdul Nabi,&nbsp;Luke Dreher,&nbsp;Jack Hartnett,&nbsp;Ashley Crossley,&nbsp;Hussein El Ghandour,&nbsp;Mayowa Osundiji,&nbsp;Hicham El Masry,&nbsp;Chadi Ayoub,&nbsp;Fadi E. Shamoun,&nbsp;Linnea M. Baudhuin","doi":"10.1155/humu/2861205","DOIUrl":"10.1155/humu/2861205","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Loeys–Dietz syndrome (LDS) is a heritable connective tissue disorder caused by pathogenic variants in genes of the transforming growth factor-&lt;i&gt;β&lt;/i&gt; (TGF-&lt;i&gt;β&lt;/i&gt;) signaling pathway. Although genotype–phenotype correlations have been suggested, comprehensive comparative data across LDS subtypes remain limited. Improved understanding of these correlations is essential to guide individualized surveillance and management strategies.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We conducted a retrospective cohort study of adults with genetically confirmed LDS evaluated between 2018 and 2024 across Mayo Clinic sites. Patients with pathogenic, likely pathogenic, or suspicious variants in &lt;i&gt;TGFBR1&lt;/i&gt;, &lt;i&gt;TGFBR2&lt;/i&gt;, or &lt;i&gt;SMAD3&lt;/i&gt; were included. Clinical characteristics, physical examination findings, cardiovascular and noncardiovascular manifestations, surgical interventions, and mortality were compared across genotypes. Categorical variables were analyzed using chi-square tests and continuous variables using parametric or nonparametric methods as appropriate.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 93 patients were included (29 &lt;i&gt;TGFBR1&lt;/i&gt;, 33 &lt;i&gt;TGFBR2&lt;/i&gt;, 31 &lt;i&gt;SMAD3&lt;/i&gt;). Demographics and mortality did not differ significantly between groups. Patients with &lt;i&gt;TGFBR1&lt;/i&gt; and &lt;i&gt;TGFBR2&lt;/i&gt; demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared with &lt;i&gt;SMAD3&lt;/i&gt; patients, though these differences were not statistically significant. Renal artery aneurysms were significantly more common in &lt;i&gt;TGFBR1&lt;/i&gt; patients (13.8%, &lt;i&gt;p&lt;/i&gt; = 0.010). SMAD3 patients had significantly higher rates of mitral regurgitation (54.8%, &lt;i&gt;p&lt;/i&gt; = 0.04), peripheral neuropathy (29.0%, &lt;i&gt;p&lt;/i&gt; = 0.018), and trends toward increased atrial fibrillation and osteoarthritis. A novel association was identified between &lt;i&gt;TGFBR1&lt;/i&gt; variants and migraine, which was significantly more prevalent in this group (62.1%, &lt;i&gt;p&lt;/i&gt; = 0.017). The rates of major cardiovascular surgical interventions were high and comparable across all genotypes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Distinct genotype–phenotype associations exist among LDS subtypes. &lt;i&gt;TGFBR1&lt;/i&gt; and &lt;i&gt;TGFBR2&lt;/i&gt; variants are associated with a greater burden of aggressive vascular disease, whereas &lt;i&gt;SMAD3&lt;/i&gt; variants are linked to mitral valve disease, peripheral neuropathy, and osteoarthritis. We also identified a novel association between &lt;i&gt;TGFBR1&lt;/i&gt; genotype and migraine. These findings reinforce the importance of","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905551","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":"Association Between Mutation Context–Associated RUNX1 Transcriptional States and Immune–Stromal Heterogeneity in Nonsmall Cell Lung Cancer","authors":"Jinyao Wang,&nbsp;Shuang Li,&nbsp;Jingjing Zhou,&nbsp;Jing Yang,&nbsp;Huan Ma","doi":"10.1155/humu/6216101","DOIUrl":"10.1155/humu/6216101","url":null,"abstract":"&lt;p&gt;Nonsmall cell lung cancer (NSCLC) is characterized by substantial heterogeneity in driver mutation backgrounds and tumor microenvironment (TME) phenotypes, yet the transcriptional regulatory states linking genotype context to immune–stromal variation remain incompletely defined. In this study, we integrated mutation, transcriptomic, and clinical data from TCGA-LUAD/LUSC to construct a mutation–expression-matched NSCLC cohort and evaluated RUNX1 as a mutation context–associated transcriptional/regulatory state rather than as a recurrently mutated driver. Driver contexts were assessed using a prespecified six-gene panel comprising EGFR, KRAS, TP53, STK11, KEAP1, and BRAF in the overall NSCLC cohort, the primary LUAD analysis, and a descriptive LUSC sensitivity analysis. The prespecified driver-context-negative operational group was defined as tumors without mutations in any of these six genes. RUNX1 mutation status was reported separately and did not contribute to this definition. Analyses included RUNX1 distributions, six-gene overlap, the RUNX1 cutoff, comutation burden, model sample-size audits, and adjusted context models. RUNX1 expression and inferred RUNX1 target-gene-set activity were evaluated across mutation contexts, whereas TME features were characterized using MCP-counter, xCell, ssGSEA, and ESTIMATE. Single-cell RNA sequencing and Visium spatial transcriptomic datasets were further used to localize RUNX1 expression, inferred target projections, and candidate TME-supporting genes. RUNX1 was prioritized within a prespecified candidate-screening framework and was significantly associated with the inferred RUNX1 target-gene-set readout. RUNX1 expression differences required interpretation in relation to histology and comutation structure. In the primary LUAD analysis, the KRAS-mutant context was associated with higher RUNX1 expression, whereas the KEAP1-mutant context was associated with lower expression. LUSC findings were retained as a descriptive sensitivity analysis and were not given the same inferential weight. Six-gene overlap, comutation burden, the RUNX1 cutoff, and model sample-size audits further showed that driver labels were nonmutually exclusive and that the prespecified driver-context-negative group was an operational reference rather than a biologically homogeneous subtype. RUNX1-high and RUNX1-low tumors displayed mutation context–dependent immune and stromal differences, involving stromal/cancer-associated fibroblast, myeloid/dendritic cell, endothelial, immune-score, and tumor-purity axes. Single-cell analysis localized RUNX1-associated signals and target-gene projections across epithelial-like and myeloid compartments, and spatial transcriptomics supported concordance between RUNX1 and selected TME-supporting genes in NSCLC tissue sections. Public immune checkpoint inhibitor cohorts were limited by small sample size and incomplete annotations and did not support RUNX1 as a stable immunotherapy-response predictor. Ove","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905567","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}