Human Mutation最新文献

{"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}

{"title":"SCN5A U12-Type Minor Intron Variant Causes Cryptic Splicing and Cardiac Arrhythmia Disease","authors":"Emma S. Singer,&nbsp;Serena Li,&nbsp;Ginell N. Ranpura,&nbsp;Seakcheng Lim,&nbsp;Sean Lal,&nbsp;Adam M. Bournazos,&nbsp;Sandra T. Cooper,&nbsp;Zachary Laksman,&nbsp;Richard D. Bagnall","doi":"10.1155/humu/4537601","DOIUrl":"10.1155/humu/4537601","url":null,"abstract":"<p>Variants affecting minor (U12-type) intron splice sites are underreported, and their consequences are poorly understood, which makes predicting their pathogenicity challenging. We investigated the impact on splicing of an <i>SCN5A</i> minor intron donor variant in an individual with cardiac arrhythmias using patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs). Genetic testing in the proband identified an <i>SCN5A</i> c.392+3A&gt;G variant of uncertain significance in a minor intron donor splice site, which segregated in affected family members with cardiac phenotypes, including Brugada syndrome. Transcriptome sequencing of proband-specific iPSC-CMs, treated with and without inhibition of nonsense-mediated decay, revealed aberrant <i>SCN5A</i> splicing. Four variant-associated isoforms were absent from control iPSC-CMs and control myectomy samples, and one skipped Exon 3 with a 96 bp extension of Exon 4. All alternatively spliced <i>SCN5A</i> transcripts were T/A cloned and confirmed by Sanger sequencing. These alternatively spliced transcripts used novel combinations of cryptic minor and major splice sites and introduced premature termination codons or an in-frame deletion, supporting reclassification of the variant as likely pathogenic. A genome-wide analysis of SpliceAI scores across minor intron splice sites retrieved from the Minor Intron Database revealed clear patterns of variants with high predicted splicing impact. This analysis also highlighted distinct splice site sequence motifs between minor and major splice sites that are not currently considered in ACMG/AMP variant interpretation guidelines. We further demonstrate that some cryptic donor–acceptor motif pairings are likely incompatible with splicing, which may inform future improvements in in silico splice site prediction tools. Integrating functional RNA sequencing with SpliceAI-based predictions at minor introns offers a pathway towards refining variant interpretation frameworks in clinical genomics.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038266","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":"Clinical and Molecular Delineation of KAT6B-Related Disorders: Novel Variants and Refined Genotype–Phenotype Correlations","authors":"Vito Luigi Colona,&nbsp;Maria Gnazzo,&nbsp;Annalidia Donato,&nbsp;Lavinia Fioretti,&nbsp;Alessandra Terracciano,&nbsp;Delia Monopoli,&nbsp;Paola Sabrina Buonuomo,&nbsp;Michaela Veronika Gonfiantini,&nbsp;Donatella Lettori,&nbsp;Roberta Taurisano,&nbsp;Tommaso Mazza,&nbsp;Daniela Concolino,&nbsp;Mafalda Mucciolo,&nbsp;Marina Macchiaiolo,&nbsp;Antonio Novelli,&nbsp;Davide Vecchio","doi":"10.1155/humu/6378376","DOIUrl":"10.1155/humu/6378376","url":null,"abstract":"<p>KAT6B-related disorders (KRDs) comprise a <i>spectrum</i> of developmental disorders ranging from Genitopatellar syndrome (GPS) to Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS), with increasing recognition of intermediate phenotypes. Although genotype–phenotype correlations have progressively emerged, the molecular basis of phenotypic variability remains incompletely understood. We performed comprehensive clinical phenotyping and trio-based whole-exome sequencing (WES) in two unrelated individuals carrying novel de novo <i>KAT6B</i> variants. Transcriptomic analysis was undertaken for the noncanonical intronic variant using peripheral blood-derived RNA. An updated review of molecularly confirmed KRDs was also performed to reassess genotype–phenotype correlations and protein domain-specific variant distribution. Patient 1 carried a novel nonsense variant (c.5347G&gt;T, p.Glu1783Ter) and presented with a predominantly SBBYSS-like phenotype. Patient 2 harbored a novel noncanonical intronic variant (c.3665-21C&gt;A) associated with a severe multisystem phenotype overlapping the GPS <i>spectrum</i>. RNA sequencing demonstrated preserved canonical exon 17–18 splicing but an approximately 50% reduction in <i>KAT6B</i> transcript abundance, supporting a dosage-sensitive pathogenic mechanism. Review of 203 published individuals identified 133 distinct pathogenic variants, confirmed exon 18 as the major mutational hotspot, and suggested domain-specific genotype–phenotype trends, including enrichment of SBBYSS-associated phenotypes among variants affecting the histone acetyltransferase (HAT) domain. Both patients also exhibited severe upper airway dysfunction with obstructive sleep apnea (OSA). These findings expand the molecular and phenotypic <i>spectrum</i> of KRDs, provide supportive transcriptomic evidence for a potential functional intronic variant, refine current genotype–phenotype correlations, and highlight upper airway dysfunction as a clinically relevant but likely underrecognized manifestation across the KRD <i>spectrum</i>.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038335","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":"Whole Genome Sequencing of Discordant Monozygotic Twins Reveals Regulatory Variants Associated With Nonsyndromic Orofacial Clefts","authors":"Emmanuel Temitope Aladenika,&nbsp;Mojisola Olujitan,&nbsp;Tamara Busch,&nbsp;Lord Gowans,&nbsp;Wasiu Adeyemo,&nbsp;Adegbayi Adeola Adekunle,&nbsp;Mekonen Eshete,&nbsp;Oluwafunmi Ajala,&nbsp;Rishitha Gadde,&nbsp;Nina Mba,&nbsp;Azeez Alade,&nbsp;Azeez Butali","doi":"10.1155/humu/2471705","DOIUrl":"10.1155/humu/2471705","url":null,"abstract":"<p>Monozygotic (MZ) twins are expected to share nearly identical genomes, yet a substantial proportion is discordant for complex diseases like nonsyndromic orofacial clefts (nsOFC). This suggests a role for postzygotic discordant genetic variations and other developmental mechanisms. In this study, we performed whole genome sequencing of two MZ twin pairs of African ancestry who were discordant for nsOFC to identify genetic variants that may contribute to phenotypic discordance. Following quality control and genotype-level filtering, we identified 37,271 variants that were present exclusively in the affected twins. Of these, 431 variants were predicted by CADD to have deleterious effects. Among these, 66 were in protein-coding regions, including 2 predicted protein-altering missense variants and splice-site variants. The remaining 365 variants were in noncoding regions including putative craniofacial enhancers. Some of these variants are rare (MAF &lt; 0.01) and were predicted to alter transcription factor binding or disrupt local chromatin architecture within putative craniofacial enhancers located near genes with established roles in craniofacial development, including <i>COL27A1</i>, <i>MPHOSPH8</i>, and <i>SPTBN1</i>. In addition, some common variants previously associated with noncraniofacial traits were also predicted to affect regulatory activity of putative craniofacial enhancers near craniofacial genes. This raises the possibility of pleiotropic regulatory effects that warrant further investigation. Overall, this study identified a set of candidate coding and regulatory variants in MZ twins discordant for nsOFC,providing targets for future functional investigations. We also proposed an overarching genetic mechanism for the prioritized discordant variants.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149037434","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}