American journal of human genetics最新文献

{"title":"Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach","authors":"Archana Rai, Jonathan Klonowski, Bo Yuan, Karen J. Coveler, Zain Dardas, Iman Egab, Jiaoyang Xu, Philip J. Lupo, A.J. Agopian, Dennis Kostka, Cecilia W. Lo, S. Stephen Yi, Bruce D. Gelb, Christine E. Seidman, Eric Boerwinkle, Jennifer E. Posey, Richard A. Gibbs, James R. Lupski, Shaine A. Morris, Zeynep Coban-Akdemir","doi":"10.1016/j.ajhg.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.014","url":null,"abstract":"Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. The genetic etiology that underlies congenital heart disease (CHD) is often unknown (less than 40%), so we used a digenic model approach for the identification of contributing variants in known laterality-defect-associated genes (<ce:italic>n</ce:italic> = 115) in the exome/genome sequencing (ES/GS) data from individuals with clinically diagnosed laterality defects. The unsolved ES/GS data were analyzed from three CHD cohorts: Baylor College of Medicine-Genomics Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR; <ce:italic>n</ce:italic>= 251 proband ES), Gabriella Miller Kids First Pediatric Research Program (Kids First; <ce:italic>n</ce:italic> = 158 trio GS), and Pediatric Cardiac Genomics Consortium (PCGC; <ce:italic>n</ce:italic> = 163 trio ES). <ce:italic>trans</ce:italic>-heterozygous digenic variants were identified in 2.8% (inherited digenic variants in 0.4%), 8.2%, and 13.5% of individuals, respectively; this was significantly higher than in 602 control trios provided by the 1000 Genomes Project (<ce:italic>p =</ce:italic> 0.001, 1.4e−07, and 8.9e−13, respectively). <ce:italic>trans</ce:italic>-heterozygous digenic variants were also identified in 0.4% and 1.4% of individuals with non-laterality CHD in Kids First and PCGC datasets, respectively, which was not statistically significant as compared to control trios (<ce:italic>p</ce:italic> = 1 and 0.059, respectively). Altogether, in laterality cohorts, 23% of digenic pairs were in the same structural complex of motile cilia. Out of 39 unique digenic pairs in laterality CHD, 29 are more likely to be potential digenic hits as predicted by the DiGePred tool. These findings provide further evidence that digenic epistatic interactions can contribute to the complex genetics of laterality defects.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying multimodal AI to physiological waveforms improves genetic prediction of cardiovascular traits","authors":"Yuchen Zhou, Justin Khasentino, Taedong Yun, Mahantesh I. Biradar, Jacqueline Shreibati, Dongbing Lai, Tae-Hwi Schwantes-An, Robert Luben, Zachary R. McCaw, Jorgen Engmann, Rui Providencia, Amand Floriaan Schmidt, Patricia B. Munroe, Howard Yang, Andrew Carroll, Anthony P. Khawaja, Cory Y. McLean, Babak Behsaz, Farhad Hormozdiari","doi":"10.1016/j.ajhg.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.015","url":null,"abstract":"Electronic health records, biobanks, and wearable biosensors enable the collection of multiple health modalities from many individuals. Access to multimodal health data provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary and overlapping information. We propose a multimodal deep learning method, multimodal representation learning for genetic discovery on low-dimensional embeddings (M-REGLE), for discovering genetic associations from a joint representation of complementary electrophysiological waveform modalities. M-REGLE jointly learns a lower representation (i.e., latent factors) of multimodal physiological waveforms using a convolutional variational autoencoder, performs genome-wide association studies (GWASs) on each latent factor, then combines the results to study the genetics of the underlying system. To validate the advantages of M-REGLE and multimodal learning, we apply it to common cardiovascular modalities (photoplethysmogram [PPG] and electrocardiogram [ECG]) and compare its results to unimodal learning methods in which representations are learned from each data modality separately but are statistically combined for downstream genetic comparison. M-REGLE identifies 19.3% more loci on the 12-lead ECG dataset, 13.0% more loci on the ECG lead I + PPG dataset, and its genetic risk score significantly outperforms the unimodal risk score at predicting cardiac phenotypes, such as atrial fibrillation (Afib), in multiple biobanks.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"101 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CADET: Enhanced transcriptome-wide association analyses in admixed samples using eQTL summary data","authors":"S. Taylor Head, Qile Dai, Joellen Schildkraut, David J. Cutler, Jingjing Yang, Michael P. Epstein","doi":"10.1016/j.ajhg.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.010","url":null,"abstract":"A transcriptome-wide association study (TWAS) is a popular statistical method for identifying genes whose genetically regulated expression (GReX) component is associated with a trait of interest. Most TWAS approaches fundamentally assume that the training dataset (used to fit the gene expression prediction model) and target genome-wide association study (GWAS) dataset are from the same ancestrally homogeneous population. If this assumption is violated, studies have shown a marked negative impact on expression prediction accuracy as well as reduced power of the downstream gene-trait association test. These issues pose a particular problem for admixed individuals whose genomes represent a mosaic of multiple continental ancestral segments. To resolve these issues, we present CADET, which enables powerful TWAS of admixed cohorts leveraging the local-ancestry (LA) information of the cohort along with summary-level expression quantitative trait locus (eQTL) data from reference panels of different ancestral groups. CADET combines multiple polygenic risk score models based on the summary-level eQTL reference data to predict LA-aware GReX components in admixed target samples. Using simulated data, we compare the imputation accuracy, power, and type I error rate of our proposed LA-aware approach to LA-unaware methods for performing TWASs. We show that CADET performs optimally in nearly all settings regardless of whether the genetic architecture of gene expression is dependent or independent of ancestry. We further illustrate CADET by performing a TWAS of 29 common blood biochemistry phenotypes within an admixed cohort from the UK Biobank and identify 18 hits unique to our LA-aware strategy, with the majority of hits supported by existing GWAS findings.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"11 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Weighing the evidence on costs and benefits of polygenic risk-based approaches in clinical practice: A systematic review of economic evaluations","authors":"Leonardo Maria Siena, Valentina Baccolini, Marianna Riccio, Annalisa Rosso, Giuseppe Migliara, Antonio Sciurti, Claudia Isonne, Jessica Iera, Francesco Pierri, Carolina Marzuillo, Corrado De Vito, Giuseppe La Torre, Paolo Villari","doi":"10.1016/j.ajhg.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.012","url":null,"abstract":"Polygenic risk scores (PRSs) represent a promising innovation in the context of precision health, but their benefits for patients and healthcare systems remain unclear. This systematic review examined the methods used to quantify the costs and benefits of PRS-based approaches across different healthcare contexts, summarizing current evidence and identifying challenges. A systematic search of three databases was conducted, and full economic evaluations related to any intervention based on polygenic risk stratification strategies were included (PROSPERO CRD42023442780). Quality was assessed using the Quality of Health Economic Studies instrument. Studies were grouped into three categories (cancer, cardiovascular disease, and other diseases), and key methodological features and characteristics were extracted. A total of 24 cost-utility analyses of generally high quality were included: 16 studies focused on cancer, five on cardiovascular disease, and three on other diseases. Studies on cancer mainly aimed to optimize screening programs, while in the other fields, PRSs were mostly used to refine eligibility for preventive therapies. Analyses were robust, but they mostly relied on hypothetical cohorts, had limited generalizability, paid insufficient attention to implementation aspects—including the delivery model—and considered only clinical benefits. Despite a positive trend toward cost effectiveness following PRS implementation, several challenges remain. These include the limited use of real-world data, issues of representativeness, and gaps in accounting for implementation costs, as well as long-term health and non-health benefits. Further research and pilot studies are needed to evaluate both the costs and benefits of PRS applications across diverse populations for multiple health outcomes simultaneously.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"20 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A data model for population descriptors in genomic research","authors":"Alyna T. Khan, Clement Adebamowo, Stephanie M. Fullerton, Jibril Hirbo, Iain R. Konigsberg, Peter Kraft, Iman Martin, Sarah C. Nelson, Michèle Ramsay, Genevieve L. Wojcik, Sally N. Adebamowo, Matthew P. Conomos, Burcu F. Darst, Micah R. Hysong, Yun Li, Alicia R. Martin, Rasika A. Mathias, Stephen S. Rich, Lori C. Sakoda, Daniel R. Schrider, Jayati Sharma, Johanna L. Smith, Quan Sun, Yuji Zhang, Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium, Stephanie M. Gogarten","doi":"10.1016/j.ajhg.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.011","url":null,"abstract":"Population descriptors used in genetic studies have broad social and translational implications. There are no globally agreed-upon definitions or usages of common population descriptors (e.g., race, ethnicity, nationality, and tribe), many of which are applied <ce:italic>ad hoc</ce:italic> and/or derived from political or bureaucratic conventions. Recent recommendations have encouraged the retention of as much granularity in population descriptors as possible during data preparation, analysis, and interpretation of research results. However, genomic research infrastructures (i.e., current practices, resources, and workflows in genomic research) often lack systematic and flexible organization, structure, and harmonization of multifaceted and detailed population descriptor data. This can lead to loss of information, barriers to international collaboration, and potential issues in clinical translation. Here, we describe a data model, developed by the NIH-funded Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium, that organizes and retains detailed population descriptor data for future research use. The model supports a versatile, traceable, and reproducible harmonization system that offers multiple benefits over existing data structures. This data model affords researchers the flexibility to thoughtfully choose and scientifically justify their choice of population descriptors. It avoids the conflation of social identities with biological categories and guards against harmful typological inferences. Genomic research tools of this kind will be crucial for producing scientifically robust findings that minimize potential harms of descriptor misuse while maximizing benefits for diverse communities.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"87 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying active and inhibitor-resistant MGMT variants for gene therapy.","authors":"Ana Cheong, Adam Fisher, Ashvin Bashyam, Anthony Forget, Robert Peters, Zachary David Nagel","doi":"10.1016/j.ajhg.2025.04.014","DOIUrl":"10.1016/j.ajhg.2025.04.014","url":null,"abstract":"<p><p>O6-methylguanine-DNA methyltransferase (MGMT) reverses alkylating-agent-induced methylation by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) at the O⁶ position of guanine. MGMT is irreversibly inhibited by O⁶-benzylguanine (O6BG), while the Pro140Lys (P140K) variant is resistant. Combining the use of O6BG/BCNU with gene transfer of MGMT P140K into hematopoietic stem cells (HSCs) has enabled in vivo enrichment of gene-modified HSCs for therapeutic effect in preclinical studies. However, the P140K substitution cannot reliably be made using currently available gene-editing approaches. Identifying functional MGMT variants that are resistant to inhibitors and amenable to gene editing would enable in vivo enrichment of HSCs edited at both MGMT and a therapeutic locus. We used computational analyses to select putative variants and generated a library of MGMT variant-expressing plasmids (pMGMTs). For our functional screen, we treated MGMT-deficient U251 cells with O6BG and co-transfected them with pMGMT together with a plasmid cocktail including a fluorescent host cell reactivation reporter plasmid (mPlum_O⁶MeG) for MGMT activity. Flow cytometric analysis of MGMT activity identified active and O6BG-resistant MGMT variants. Treatment with a second MGMT inhibitor, PaTrin-2, confirmed these results. We also found MGMT variants that are detectable in the general population and tumors to be active and O6BG sensitive. Taken together, our findings establish a functional database for MGMT variants and a cell-based platform for screening DNA-repair proteins for unknown functional properties.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1430-1446"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity.","authors":"Teng Hiang Heng, Klaudia Walter, Qin Qin Huang, Juha Karjalainen, Mark J Daly, Henrike O Heyne, Daniel S Malawsky, Georgios Kalantzis, Sarah Finer, David A van Heel, Hilary C Martin","doi":"10.1016/j.ajhg.2025.03.020","DOIUrl":"10.1016/j.ajhg.2025.03.020","url":null,"abstract":"<p><p>Genetic association studies have focused on testing additive models in cohorts with European ancestry. Little is known about recessive effects on common diseases, specifically for non-European ancestry. Genes & Health is a cohort of British Pakistani and Bangladeshi individuals with elevated rates of consanguinity and endogamy, making it suitable to study recessive effects. We imputed variants into a genotyped dataset (n = 44,190) by using two reference panels: a set of 4,982 whole-exome sequences from within the cohort and the Trans-Omics for Precision Medicine (TOPMed-r2) panel. We performed association testing with 898 diseases from electronic health records. 185 independent loci reached genome-wide significance (p < 5 × 10^-8) under the recessive model, with p values lower than under the additive model, and >40% of these were novel. 140 loci demonstrated nominally significant (p < 0.05) dominance deviation p values, confirming a recessive association pattern. Sixteen loci in three clusters were significant at a Bonferroni threshold, accounting for multiple phenotypes tested (p < 5.4 × 10^-12). In FinnGen, we replicated 44% of the expected number of Bonferroni-significant loci we were powered to replicate, at least one from each cluster, including an intronic variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3; rs66812091) and non-alcoholic fatty liver disease, a previously reported additive association. We present evidence suggesting that the association is recessive instead (odds ratio [OR] = 1.3, recessive p = 2 × 10^-12, additive p = 2 × 10^-11, dominance deviation p = 3 × 10^-2, and FinnGen recessive OR = 1.3 and p = 6 × 10^-12). We identified a novel protective recessive association between a missense variant in SGLT4 (rs61746559), a sodium-glucose transporter with a possible role in the renin-angiotensin-aldosterone system, and hypertension (OR = 0.2, p = 3 × 10^-8, dominance deviation p = 7 × 10^-6). These results motivate interrogating recessive effects on common diseases more widely.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1316-1329"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing precision care in pregnancy through a treatable fetal findings list.","authors":"Jennifer L Cohen, Michael Duyzend, Sophia M Adelson, Julie Yeo, Mark Fleming, Rebecca Ganetzky, Rebecca Hale, Deborah M Mitchell, Sarah U Morton, Rebecca Reimers, Amy Roberts, Alanna Strong, Weizhen Tan, Jay R Thiagarajah, Melissa A Walker, Robert C Green, Nina B Gold","doi":"10.1016/j.ajhg.2025.03.011","DOIUrl":"10.1016/j.ajhg.2025.03.011","url":null,"abstract":"<p><p>The use of genomic sequencing (GS) for prenatal diagnosis of fetuses with sonographic abnormalities has grown tremendously over the past decade. Fetal GS also offers an opportunity to identify incidental genomic variants that are unrelated to the fetal phenotype but may be relevant to fetal and newborn health. There are currently no guidelines for reporting incidental findings from fetal GS. In the United States, GS for adults and children is recommended to include a list of \"secondary findings\" genes (ACMG SF v.3.2) that are associated with disorders for which surveillance or treatment can reduce morbidity and mortality. The genes on ACMG SF v.3.2 predominantly cause adult-onset disorders. Importantly, many genetic disorders with fetal and infantile onset are treatable as well. A proposed solution is to create a \"treatable fetal findings list,\" which can be offered to pregnant individuals undergoing fetal GS or, eventually, as a standalone cell-free fetal DNA screening test. In this integrative review, we propose criteria for a treatable fetal findings list, then identify genetic disorders with clinically available or emerging fetal interventions and those for which clinical detection and intervention in the first week of life might lead to improved outcomes. Finally, we synthesize the potential benefits, limitations, and risks of a treatable fetal findings list.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1251-1269"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of non-coding variants associated with transcription-factor binding through ATAC-seq-defined footprint QTLs in liver.","authors":"Max F Dudek, Brandon M Wenz, Christopher D Brown, Benjamin F Voight, Laura Almasy, Struan F A Grant","doi":"10.1016/j.ajhg.2025.03.019","DOIUrl":"10.1016/j.ajhg.2025.03.019","url":null,"abstract":"<p><p>Non-coding variants discovered by genome-wide association studies (GWASs) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease association and the disruption of cis-regulatory sequences. Occupancy of a TF inside a region of open chromatin can be detected in ATAC-seq where bound TFs block the transposase Tn5, leaving a pattern of relatively depleted Tn5 insertions known as a \"footprint.\" Here, we sought to identify variants associated with TF binding, or \"footprint quantitative trait loci\" (fpQTLs), in ATAC-seq data generated from 170 human liver samples. We used computational tools to scan the ATAC-seq reads to quantify TF binding likelihood as \"footprint scores\" at variants derived from whole-genome sequencing generated in the same samples. We tested for association between genotype and footprint score and observed 809 fpQTLs associated with footprint-inferred TF binding (FDR < 5%). Given that Tn5 insertion sites are measured with base-pair resolution, we show that fpQTLs can aid GWAS and QTL fine-mapping by precisely pinpointing TF activity within broad trait-associated loci where the underlying causal variant is unknown. Liver fpQTLs were strongly enriched across ChIP-seq peaks, liver expression QTLs (eQTLs), and liver-related GWAS loci, and their inferred effect on TF binding was concordant with their effect on underlying sequence motifs in 78% of cases. We conclude that fpQTLs can reveal causal GWAS variants, define the role of TF binding-site disruption in complex traits, and provide functional insights into non-coding variants, ultimately informing novel treatments for common diseases.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1302-1315"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder.","authors":"María Del Rocío Pérez Baca, María Palomares-Bralo, Michiel Vanhooydonck, Lisa Hamerlinck, Eva D'haene, Sebastian Leimbacher, Eva Z Jacobs, Laurenz De Cock, Erika D'haenens, Annelies Dheedene, Zoë Malfait, Lies Vantomme, Ananilia Silva, Kathleen Rooney, Xiaonan Zhao, Amir Hossein Saeidian, Nichole Marie Owen, Fernando Santos-Simarro, Roser Lleuger-Pujol, Sixto García-Miñaúr, Itsaso Losantos-García, Björn Menten, Gaia Gestri, Nicola Ragge, Bekim Sadikovic, Elke Bogaert, Kris Vleminckx, Thomas Naert, Delfien Syx, Bert Callewaert, Sarah Vergult","doi":"10.1016/j.ajhg.2025.04.008","DOIUrl":"10.1016/j.ajhg.2025.04.008","url":null,"abstract":"<p><p>8q21.11 microdeletions involving ZFHX4 have previously been associated with a syndromic form of intellectual disability, hypotonia, unstable gait, and hearing loss. We report on 63 individuals-57 probands and 6 affected family members-with protein-truncating variants (n = 41), (micro)deletions (n = 21), or an inversion (n = 1) affecting ZFHX4. Probands display variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function (LoF) variants largely overlap, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions. ZFHX4 shows increased expression during human brain development and neuronal differentiation. Furthermore, ZFHX4-interacting factors identified via immunoprecipitation followed by mass spectrometry (IP-MS) suggest an important role for ZFHX4 in cellular pathways, especially during histone modifications, protein trafficking, signal transduction, cytosolic transport, and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds the promoter of genes with crucial roles in embryonic, neuronal, and axonal development. Moreover, we investigated whether the disruption of zfhx4 causes craniofacial abnormalities in zebrafish. First-generation (F0) zfhx4 crispant zebrafish, a (mosaic) mutant for zfhx4 LoF variants, have significantly shorter Meckel's cartilage and smaller ethmoid plates compared to control zebrafish. Behavioral assays showed a decreased movement frequency in the zfhx4 crispant zebrafish in comparison with controls. Furthermore, structural abnormalities were found in the zebrafish hindbrain. In conclusion, our findings delineate a ZFHX4-associated neurodevelopmental disorder and suggest a role for zfhx4 in facial skeleton patterning, palatal development, and behavior.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1388-1414"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}