Human molecular genetics最新文献

{"title":"Optical genome mapping identifies cryptic balanced chromosomal rearrangements in karyotypically normal couples with recurrent pregnancy loss or adverse pregnancy history.","authors":"Lijuan Wang, Ming Gao, Jiahui Ma, Kexin Shi, Ziyu Wei, Qian Sun, Xiaowei Chen, Sexin Huang, Yang Zou, Peiwen Xu, Wenkai Ji, Bingqing Zhao, Keliang Wu, Junhao Yan, Xuan Gao, Zi-Jiang Chen, Xia Luo, Yuan Gao","doi":"10.1093/hmg/ddag091","DOIUrl":"https://doi.org/10.1093/hmg/ddag091","url":null,"abstract":"<p><p>Recurrent pregnancy loss affects 1%-2% of reproductive-aged couples, with chromosomal abnormalities accounting for 40%-60% of cases. There is a close link between adverse pregnancy history (APH) and recurrent pregnancy loss (RPL). However, cryptic balanced translocations with translocated fragments smaller than the resolution of karyotyping or with similar banding patterns are often missed. This study, based on the testing results of 586 families who underwent preimplantation genetic testing for aneuploidy (PGT-A) due to RPL or APH, identified cryptic balanced translocations that were not detectable by conventional karyotyping, and validated them using Optical Genome Mapping (OGM). The prevalence of cryptic balanced translocations in the overall RPL/APH cohort was 1.19% (7/586, 95% CI: 0.58%-2.45%, Wilson score). It determined the incidence of cryptic balanced translocations in RPL or APH and changed the clinical management of these patients. Additionally, OGM resolved a 4-chromosome complex chromosomal rearrangement (CCR) involving 6 breakpoints and elucidated the genetic basis of two whole-exome sequencing-negative monogenic disorders by demonstrating pathogenic disruptions of EXT1 and PITX2 genes. OGM can be used as a second-line diagnostic tool, in addition to karyotype analysis and CNV-seq, for etiological screening of couples with recurrent pregnancy loss and adverse pregnancy history. The main conclusion of this study is that OGM can identify cryptic structural rearrangements, thereby enabling timely conversion of clinical management from PGT-A to preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR), and facilitating the transfer of euploid, non-carrier embryos for couples with RPL or APH.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 19","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep phenotyping of EHMT1 ankyrin repeat domain missense variants in Kleefstra syndrome by multi-tiered structural genomics analyses at atomic resolution.","authors":"Karina L Bursch, Young-In Chi, Jacob Licklider, Davin R Jensen, Audrey E Catlin, Michael T Zimmermann, Gwen Lomberk, Raul A Urrutia, Brian C Smith","doi":"10.1093/hmg/ddag094","DOIUrl":"10.1093/hmg/ddag094","url":null,"abstract":"<p><p>EHMT1 is a lysine methyltransferase that writes and reads histone methylation marks to repress transcription. Deleterious mutations in EHMT1 cause Kleefstra syndrome (KLEFS1; OMIM #610253), a congenital neurodevelopmental disorder. Many of these affect the ankyrin repeat (ANKR) domain, which recognizes histone H3 lysine-9 methylation and mediates interactions with other epigenetic regulators. However, the functional consequences of EHMT1 missense variants within the ANKR domain remain poorly characterized, as nearly 50% are currently classified as variants of unknown significance (VUS). To address this gap, we performed a comprehensive structural genomics analysis to predict how 56 Kleefstra syndrome-associated missense variants alter EHMT1 ANKR domain structure and function. We integrated sequence-based pathogenicity algorithms with protein structural and dynamics metrics to generate variant molecular fitness scores. From these predictions, we selected 16 representative variants for experimental validation. Using differential scanning fluorimetry and circular dichroism, we quantified variant-specific effects on ANKR domain stability and secondary structure. We further assessed methyl-lysine binding using fluorescence polarization assays. By combining computational and biochemical analyses, we re-classified 80% of VUS as tolerated or damaging based on their effects on ANKR domain structural integrity and methyl-lysine binding. The resulting molecular fitness scores reveal mechanisms by which damaging variants disrupt EHMT1 ANKR domain stability, ligand binding, or both. Together, our integrated approach refines EHMT1 variant annotation and provides mechanistic insights that enhance current tools for variant interpretation in Kleefstra syndrome, which can be translated to missense variants in other epigenetic proteins and rare diseases.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis of mucopolysaccharidosis IVA in a large cohort: genotype-phenotype correlations and reporting of 12 novel GALNS variants.","authors":"Xi Yin, Yiqi Qin, Xueying Su, Qianqian Deng, Chengxi Li, Xiaoyuan Zhao, Chunhua Zeng, Cuili Liang, Yanna Cai, Yongxian Shao, Yonglan Huang, Li Liu, Wen Zhang","doi":"10.1093/hmg/ddag101","DOIUrl":"https://doi.org/10.1093/hmg/ddag101","url":null,"abstract":"<p><p>Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS). In this single-center study, we analyzed the clinical and genetic characteristics of 82 pediatric MPS IVA patients, including 68 severe, 12 intermediate, and 2 mild cases. The most common clinical manifestations were pectus carinatum (72%), short stature (56%), and genu valgum (45%). All patients showed markedly reduced GALNS activity, although no significant difference was observed across phenotypic subgroups. Genetic analysis identified 66 distinct GALNS variants, 12 of which were novel. The c.953T>G (p.M318R) variant was the most frequent allele (24.7%). Based on integrated clinical, structural, and in silico assessments, p.M318R and p.R386C were linked to severe disease, whereas p.P499L was associated with mild phenotypes. Protein structure analysis revealed that all homozygous missense variants located in domain 1 correlated with severe presentations. Among patients carrying two missense variants, 85% (34/40) exhibited severe symptoms, and 70.6% (24/34) of these had at least one variant affecting buried residues. Notably, 85.7% (24/28) of patients with biallelic buried-residue missense variants were classified as severe. In summary, this study delineates the phenotypic spectrum of MPS IVA, expands its genotypic landscape, and provides a foundation for further genotype-phenotype investigations.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-type-specific dysregulated gene expression in the frontal cortex of an Angelman syndrome pig model.","authors":"Ashley Coffell, Livia Schuller, Sarah Christian, Scott V Dindot","doi":"10.1093/hmg/ddag092","DOIUrl":"10.1093/hmg/ddag092","url":null,"abstract":"<p><p>Angelman syndrome is a neurodevelopmental disorder caused by the loss of the maternal allele of the ubiquitin-protein ligase E3A (UBE3A) gene. UBE3A is imprinted with maternal-allelic expression in neurons of the central nervous system (CNS) and biallelic expression in other cell types. Consequently, in Angelman syndrome, UBE3A is substantially reduced in CNS neurons and reduced by half in other cells. It is unclear how cell-type-specific gene expression in the brain is dysregulated in Angelman syndrome, as previous studies have lacked cell type resolution. Using single nuclei RNA-sequencing, we show that gene expression is dysregulated in neuronal subtypes in the frontal cortex of neonatal pigs with a UBE3A maternal deletion. A total of 3812 unique genes were dysregulated across ten cell type clusters, with most of the dysregulated genes (3154 genes) in excitatory neurons. Pathway analysis revealed alterations in oxidative phosphorylation, proteasome function, and synaptic function. Additionally, somatostatin (SST)-a secreted neuropeptide involved in GABAergic inhibition and synaptic plasticity- was reduced in inhibitory neurons in the cortex and hypothalamus, which correlated with lower circulating SST protein in neonates but not adolescent pigs. Overall, these findings provide greater clarity on the cell-type-specific dysregulation of gene expression and cellular pathways caused by the loss of UBE3A in CNS neurons, expanding our understanding of the molecular pathology in Angelman syndrome.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 19","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.","authors":"Timothy J Hines, Jonathan R Funke, Samia L Pratt, Alaura D Rice, Jeffery L Twiss, Robert W Burgess","doi":"10.1093/hmg/ddag084","DOIUrl":"10.1093/hmg/ddag084","url":null,"abstract":"<p><p>Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6 J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6 J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 18","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo dissection of human NRXN1 isoforms reveals gain-of-function pathogenicity of schizophrenia-associated 3' deletions.","authors":"Dustin Haskell, Michael P Hart","doi":"10.1093/hmg/ddag085","DOIUrl":"10.1093/hmg/ddag085","url":null,"abstract":"<p><p>Heterozygous deletions in NRXN1, encoding the presynaptic adhesion molecule Neurexin 1, are among the most frequently identified rare variants in schizophrenia and other neuropsychiatric disorders. Patient sequencing has revealed that 3' deletions within NRXN1 generate novel isoforms not produced from the intact locus, yet whether these isoforms are functional, passively non-functional, or actively pathogenic in vivo is still not clear. To address this, we expressed eight human NRXN1 isoforms in C. elegans neurons including four control isoforms and four 3' deletion variant isoforms identified in schizophrenia patient cell lines, and characterized their effects on protein localization and two independent behaviors: a food deprivation response and social feeding behaviors. Most human isoforms showed expression and localization within the nerve ring and neurons similar to the C. elegans ortholog, NRX-1; however, several isoforms, particularly among the 3' deletion variants, displayed aberrant accumulation in neuronal cell bodies or as puncta in neuropil. Functionally, isoforms fell into one of three categories: no effect on nrx-1 loss-of-function behavioral phenotypes, partial rescue, or gain of function, with multiple isoforms showing differences between the behaviors. Strikingly, two 3' deletion isoforms produced gain-of-function behavioral phenotypes more severe than the nrx-1 null mutant, demonstrating that these patient-derived variants can be actively pathogenic. These results establish C. elegans as a tractable in vivo platform for dissecting the isoform-specific functional consequences of NRXN1 variants and suggest that strategies for NRXN1-associated neuropsychiatric diseases must account for both loss-of-function and gain-of-function isoform mechanisms.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 18","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and mechanistic origins of genome-wide ploidy abnormalities in ICSI derived human preimplantation embryos.","authors":"Giancarlo Mancuso, Olga Tšuiko, Sophie Debrock, Arne Vanhie, Karen Peeraer, Hilde Van Esch, Eftychia Dimitriadou, Joris Robert Vermeesch","doi":"10.1093/hmg/ddag083","DOIUrl":"https://doi.org/10.1093/hmg/ddag083","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide ploidy abnormalities (GWPA) constitute a distinct and clinically significant class of chromosomal errors that arise during human preimplantation development. However, the developmental origins and prevalence of GWPA remain incomplete and poorly understood.</p><p><strong>Methods: </strong>To evaluate the frequency and origin of GWPA in human embryos, we have retrieved preimplantation genetic testing (PGT) haplotyping data, derived from 3798 blastomere and 3593 trophectoderm biopsies. Prior haplotype reconstruction and determination of parental origin were performed using B-allele frequency-aware haplotyping (haplarithmisis).</p><p><strong>Results: </strong>GWPA were detected in 113 biopsies: 81 cleavage-stage embryos and 32 blastocysts. Genome-wide loss of heterozygosity of maternal origin was the most frequent abnormality. Triploidy was the second most common aberration present in 35 embryos: 24 cleavage-stage embryos and 11 blastocysts, with the majority resulting from maternal meiosis II errors. In addition, we uncover less-characterized abnormalities, providing new insights into the chromosomal mechanisms driving early human embryonic development.</p><p><strong>Conclusions: </strong>GWPA occur in 2.16% of cleavage-stage and 0.89% of blastocyst-stage ICSI embryos, showing a strong selection against GWPA during preimplantation development. This study also demonstrates that using appropriate methods to detect GWPA when screening ICSI embryos can help prevent the transfer of nonviable embryos.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 18","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myofibrillar myopathy-associated KY protein promotes muscle fibre size rescue independent of its predicted catalytic triad.","authors":"Ahmed Nouh, Oscar Harrad, Andrzej M Brzozowski, William Grey, Gonzalo Blanco","doi":"10.1093/hmg/ddag086","DOIUrl":"https://doi.org/10.1093/hmg/ddag086","url":null,"abstract":"<p><p>Mutations in the Ky gene are the underlying cause of Myofibrillar Myopathy-7 (MFM-7), a rare progressive muscle weakness disease of childhood onset. A defining characteristic of the KY protein is the presence of a conserved transglutaminase-like domain, but unequivocal evidence of its enzymatic function remains to be established. To investigate the functional relevance of the predicted KY catalytic triad we use here in vitro enzymatic assays, structural modeling and in vivo rescue experiments in ky/ky mice. While structural modelling shows a striking conservation of the catalytic pocket architecture, our results show that recombinant KY proteins showed no detectable enzymatic activity under the assay conditions used. Moreover, while deletion of transglutaminase-like domain prevents phenotype rescue, replacements of the predicted catalytic residues do not impair the protein's ability to rescue fibre size in ky/ky muscle, indicating that the predicted catalytic residues are dispensable for fibre size rescue in these assays. Proteomic analyses identified KY-associated protein complexes involved in protein quality control, including core components of the Chaperone-Assisted Selective Autophagy machinery. In agreement, basal autophagic flux is significantly reduced in both KY-deficient C2C12 cells and ky/ky muscle fibres. Collectively, our data suggests that the TGN/PROT domain facilitates critical molecular associations at the sarcomeric Z-disc through a mechanism independent of catalysis and that impaired autophagic flux may contribute to the muscle phenotype.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 18","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy.","authors":"Alice Moncheaux, Alain Guimond, Coralie Spiegelhalter, Nadia Messaddeq, Chadia Nahy, Jocelyn Laporte","doi":"10.1093/hmg/ddag082","DOIUrl":"https://doi.org/10.1093/hmg/ddag082","url":null,"abstract":"<p><p>Mutations in CAV3, encoding caveolin-3, cause caveolinopathies, rare genetic disorders affecting both skeletal and cardiac muscle. Caveolin-3 contributes to T-tubule formation and excitation-contraction coupling. To date, there are no therapy for caveolinopathies. BIN1 (amphiphysin 2), a membrane-shaping protein critical for T-tubule integrity, has shown therapeutic promise in congenital myopathies and heart dysfunction. We evaluated the therapeutic impact of BIN1 overexpression in Cav-3 knockout mice, a model recapitulating key features of human caveolinopathy. We assessed skeletal and cardiac function, T-tubule morphology, mitochondria, and gene expression using histological, physiological, and molecular approaches. Results: We found Cav-3-/- mice displayed skeletal muscle weakness, T-tubule disorganization, and mitochondrial abnormalities, alongside cardiac diastolic dysfunction and myofibrillar disarray. While BIN1 overexpression failed to improve muscle strength, T-tubule structure, or fiber atrophy, it corrected nuclear positioning and partially restored mitochondrial markers in skeletal muscle. In contrast, BIN1 robustly rescued cardiac performance, restoring end-diastolic volume, cardiac output, and sarcomeric integrity. Expression profiling revealed greater dysregulation of excitation-contraction coupling and atrogene pathways in skeletal than in cardiac muscle in Cav-3-/- mice. Cavin-4, a BIN1-interacting protein and caveolar component, was selectively dysregulated in Cav-3-/- muscle, suggesting a mechanistic barrier to BIN1-mediated rescue in this tissue. These findings identify tissue-specific differences in the molecular consequences of caveolin-3 loss and demonstrate that BIN1 overexpression effectively rescues cardiac manifestations of caveolinopathy while only partially ameliorating the associated subcellular defects in skeletal muscle. Our results support BIN1 investigation as a potential target for inherited cardiomyopathies, while highlighting the need for alternative strategies in skeletal muscle.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 18","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PONG 2.0: allele imputation for the killer cell immunoglobulin-like receptors.","authors":"Suraju A Sadeeq, Laura A Leaton, Katherine M Kichula, Ticiana D J Farias, Neus Font-Porterias, Nicholas R Pollock, Christopher E Collora, Erick C Castelli, Christopher R Gignoux, Paul J Norman","doi":"10.1093/hmg/ddag075","DOIUrl":"https://doi.org/10.1093/hmg/ddag075","url":null,"abstract":"<p><p>Killer cell immunoglobulin-like receptors (KIRs) are polymorphic immune regulators that modulate natural killer and T cell responses via interactions with human leukocyte antigen (HLA) class I ligands. High combinatorial diversity of KIR and HLA influences infection, autoimmunity, cancer, transplantation, and reproductive success. Although comprehensive KIR genotyping is achievable through targeted sequencing, complex genomic architecture hampers large-scale disease studies using genome wide data. Here, we introduce PONG2.0, a computational framework that accurately imputes high-resolution genotypes for all KIR that interact with HLA, directly from SNP-array data. We trained multi-ancestry models using matched SNP and KIR alleles from a subset of the 1000 Genomes Project (EUR = 187, AMR = 93, SAS = 102, AFR = 102, EAS = 102), achieving 92-99% overall accuracy. Validation against targeted sequencing of 267 independent samples confirmed robust per-locus concordance (92.1-97.7%). Population-level benchmarking of > 8000 individuals showed strong agreement with targeted sequencing (R2 up to 0.999; median deviation 0.6-6.8%), demonstrating reliable genotyping of samples that were independent from the model-building data. PONG2.0 is implemented as an open-source R package with pre-trained models, providing an efficient and scalable solution for KIR immunogenetics in large-scale biobanks and cohort studies. https://github.com/NormanLabUCD/PONG2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}