American journal of human genetics最新文献

{"title":"Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum.","authors":"Iris Verbinnen, Sofia Douzgou Houge, Tzung-Chien Hsieh, Hellen Lesmann, Aron Kirchhoff, David Geneviève, Elise Brimble, Lisa Lenaerts, Dorien Haesen, Rebecca J Levy, Julien Thevenon, Laurence Faivre, Elysa Marco, Jessica X Chong, Mike Bamshad, Karynne Patterson, Ghayda M Mirzaa, Kimberly Foss, William Dobyns, Susan M White, Lynn Pais, Emily O'Heir, Raphaela Itzikowitz, Kirsten A Donald, Celia Van der Merwe, Alessandro Mussa, Raffaela Cervini, Elisa Giorgio, Tony Roscioli, Kerith-Rae Dias, Carey-Anne Evans, Natasha J Brown, Anna Ruiz, Juan Pablo Trujillo Quintero, Rachel Rabin, John Pappas, Hai Yuan, Katherine Lachlan, Simon Thomas, Anita Devlin, Michael Wright, Richard Martin, Joanna Karwowska, Renata Posmyk, Nicolas Chatron, Zornitza Stark, Oliver Heath, Martin Delatycki, Rebecca Buchert, Georg-Christoph Korenke, Keri Ramsey, Vinodh Narayanan, Dorothy K Grange, Judith L Weisenberg, Tobias B Haack, Stephanie Karch, Patricia Kipkemoi, Moses Mangi, Karen G C B Bindels de Heus, Marie-Claire Y de Wit, Tahsin Stefan Barakat, Derek Lim, Géraldine Van Winckel, Rebecca C Spillmann, Vandana Shashi, Maureen Jacob, Antonia M Stehr, Peter Krawitz, Gunnar Douzgos Houge, Veerle Janssens","doi":"10.1016/j.ajhg.2025.01.021","DOIUrl":"10.1016/j.ajhg.2025.01.021","url":null,"abstract":"<p><p>Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"554-571"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomics reveals inter-ethnic variation in immune response to Falciparum malaria.","authors":"Tala Shahin, Jakub Jurkovic, Mame Massar Dieng, Vinu Manikandan, Wael Abdrabou, Bana Alamad, Odmaa Bayaraa, Aïssatou Diawara, Samuel Sindié Sermé, Noëlie Béré Henry, Salif Sombie, Dareen Almojil, Marc Arnoux, Nizar Drou, Issiaka Soulama, Youssef Idaghdour","doi":"10.1016/j.ajhg.2025.01.020","DOIUrl":"10.1016/j.ajhg.2025.01.020","url":null,"abstract":"<p><p>Africa's environmental, cultural, and genetic diversity can profoundly shape population responses to infectious diseases, including malaria caused by Plasmodium falciparum. Differences in malaria susceptibility among populations are documented, but the underlying mechanisms remain poorly understood. Notably, the Fulani ethnic group in Africa is less susceptible to malaria compared to other sympatric groups, such as the Mossi. They exhibit lower disease rates and parasite load as well as enhanced serological protection. However, elucidating the molecular and cellular basis of this protection has been challenging in part due to limited immunological characterization at the cellular level. To address this question, we performed single-cell transcriptomic profiling of peripheral blood mononuclear cells from 126 infected and non-infected Fulani and Mossi children in rural Burkina Faso. This analysis generated over 70,000 single-cell transcriptomes and identified 30 distinct cell subtypes. We report a profound effect of ethnicity on the transcriptional landscape, particularly within monocyte populations. Differential expression analysis across cell subtypes revealed ethnic-specific immune signatures under both infected and non-infected states. Specifically, monocytes and T cell subtypes of the Fulani exhibited reduced pro-inflammatory responses, while their B cell subtypes displayed stronger activation and inflammatory profiles. Furthermore, single-cell expression quantitative trait locus (eQTL) analysis in monocytes of infected children revealed several significant regulatory variants with ethnicity-specific effects on immune-related genes, including CD36 and MT2A. Overall, we identify ethnic, cell-type-specific, and genetic regulatory effects on host immune responses to malaria and provide valuable single-cell eQTL and transcriptomic datasets from under-represented populations.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"709-723"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 ASHG Scientific Achievement Award.","authors":"Nadav Ahituv","doi":"10.1016/j.ajhg.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.005","url":null,"abstract":"<p><p>This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. The video of the original address can be found at the ASHG website.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 3","pages":"473-477"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584363","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":"Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.","authors":"Meltem Ece Kars, David Stein, Peter D Stenson, David N Cooper, Wendy K Chung, Peter J Gruber, Christine E Seidman, Yufeng Shen, Martin Tristani-Firouzi, Bruce D Gelb, Yuval Itan","doi":"10.1016/j.ajhg.2025.01.024","DOIUrl":"10.1016/j.ajhg.2025.01.024","url":null,"abstract":"<p><p>Congenital heart disease (CHD) is the most common congenital anomaly and a leading cause of infant morbidity and mortality. Despite extensive exploration of the monogenic causes of CHD over the last decades, ∼55% of cases still lack a molecular diagnosis. Investigating digenic interactions, the simplest form of oligogenic interactions, using high-throughput sequencing data can elucidate additional genetic factors contributing to the disease. Here, we conducted a comprehensive analysis of digenic interactions in CHD by utilizing a large CHD trio exome sequencing cohort, comprising 3,910 CHD and 3,644 control trios. We extracted pairs of presumably deleterious rare variants observed in CHD-affected and unaffected children but not in a single parent. Burden testing of gene pairs derived from these variant pairs revealed 29 nominally significant gene pairs. These gene pairs showed a significant enrichment for known CHD genes (p < 1.0 × 10^-4) and exhibited a shorter average biological distance to known CHD genes than expected by chance (p = 3.0 × 10^-4). Utilizing three complementary biological relatedness approaches including network analyses, biological distance calculations, and candidate gene prioritization methods, we prioritized 10 final gene pairs that are likely to underlie CHD. Analysis of bulk RNA-sequencing data showed that these genes are highly expressed in the developing embryonic heart (p < 1 × 10^-4). In conclusion, our findings suggest the potential role of digenic interactions in CHD pathogenesis and provide insights into unresolved molecular diagnoses. We suggest that the application of the digenic approach to additional disease cohorts will significantly enhance genetic discovery rates.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"583-598"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic association studies using disease liabilities from deep neural networks.","authors":"Lu Yang, Marie C Sadler, Russ B Altman","doi":"10.1016/j.ajhg.2025.01.019","DOIUrl":"10.1016/j.ajhg.2025.01.019","url":null,"abstract":"<p><p>The case-control study is a widely used method for investigating the genetic underpinnings of binary traits. However, long-term, prospective cohort studies often grapple with absent or evolving health-related outcomes. Here, we propose two methods, liability and meta, for conducting genome-wide association studies (GWASs) that leverage disease liabilities calculated from deep patient phenotyping. Analyzing 38 common traits in ∼300,000 UK Biobank participants, we identified an increased number of loci in comparison to the number identified by the conventional case-control approach, and there were high replication rates in larger external GWASs. Further analyses confirmed the disease specificity of the genetic architecture; the meta method demonstrated higher robustness when phenotypes were imputed with low accuracy. Additionally, polygenic risk scores based on disease liabilities more effectively predicted newly diagnosed cases in the 2022 dataset, which were controls in the earlier 2019 dataset. Our findings demonstrate that integrating high-dimensional phenotypic data into deep neural networks enhances genetic association studies while capturing disease-relevant genetic architecture.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"675-692"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inter-chromosomal insertions at Xq27.1 associated with retinal dystrophy induce dysregulation of LINC00632 and CDR1as/ciRS-7.","authors":"Jessica C Gardner, Katarina Jovanovic, Daniele Ottaviani, Uirá Souto Melo, Joshua Jackson, Rosellina Guarascio, Kalliopi Ziaka, Kwan-Leong Hau, Amelia Lane, Rachel L Taylor, Niuzheng Chai, Christina Gkertsou, Owen Fernando, Monika Piwecka, Michalis Georgiou, Stefan Mundlos, Graeme C Black, Anthony T Moore, Michel Michaelides, Michael E Cheetham, Alison J Hardcastle","doi":"10.1016/j.ajhg.2025.01.007","DOIUrl":"10.1016/j.ajhg.2025.01.007","url":null,"abstract":"<p><p>In two unrelated families with X-linked inherited retinal dystrophy, identification of the causative variants was elusive. Interrogation of the next-generation sequencing (NGS) data revealed a \"dark\" intergenic region on Xq27.1 with poor coverage. Long-range PCR and DNA walking across this region revealed different inter-chromosomal insertions into the human-specific palindrome on Xq27.1: a 58 kb insertion of 9p24.3 [der(X)dir ins(X;9)(q27.1;p24.3)] in family 1 and a 169 kb insertion of 3p14.2 [der(X)inv ins(X;3)(q27.1;p14.2)] in family 2. To explore the functional consequence of these structural variants in genomic and cellular contexts, induced pluripotent stem cells were derived from affected and control fibroblasts and differentiated to retinal organoids (ROs) and retinal pigment epithelium. Transcriptional dysregulation was evaluated using RNA sequencing (RNA-seq) and RT-qPCR. A downstream long non-coding RNA, LINC00632 (Xq27.1), was upregulated in ROs from both families compared to control samples. In contrast, the circular RNA CDR1as/ciRS-7 (circular RNA sponge for miR-7), spliced from linear LINC00632, was downregulated. To investigate this tissue-specific dysregulation, we interrogated the landscape of the locus using Hi-C and cleavage under targets and tagmentation sequencing (CUT&Tag). This revealed active retinal enhancers within the insertions within a topologically associated domain that also contained the upstream promoter of LINC00632, permitting ectopic contact. Furthermore, CDR1as/ciRS-7 acts as a \"sponge\" for miR-7, and target genes of miR-7 were also dysregulated in ROs derived from both families. We describe a new genomic mechanism for retinal dystrophy, and our data support a convergent tissue-specific mechanism of altered regulation of LINC00632 and CDR1as/ciRS-7 as a consequence of the insertions within the palindrome on Xq27.1.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"523-536"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of CNTN2 as a genetic modifier of PIGA-CDG in a family with incomplete penetrance and in Drosophila.","authors":"Holly J Thorpe, Brent S Pedersen, Miranda Dietze, Nichole Link, Aaron R Quinlan, Joshua L Bonkowsky, Ashley Thomas, Clement Y Chow","doi":"10.1016/j.ajhg.2025.01.017","DOIUrl":"10.1016/j.ajhg.2025.01.017","url":null,"abstract":"<p><p>Loss-of-function mutations in the X chromosome gene PIGA lead to phosphatidylinositol glycan class A congenital disorder of glycosylation (PIGA-CDG), an ultra-rare CDG typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA c.395C>G (p.Ser132Cys), an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great uncle also carry the same PIGA variant, but neither presents with symptoms associated with PIGA-CDG. We hypothesized that genetic modifiers might contribute to this reduced penetrance. Using whole-genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in the carriers and possible protective variants found in the carriers and not in the probands. Candidate genetic modifier variants included heterozygous, damaging variants in three genes involved directly in glycosylphosphatidylinositol (GPI)-anchor biosynthesis and additional variants in other glycosylation pathways or encoding GPI-anchored proteins. Using a Drosophila eye-based model, we tested modifiers identified through genome sequencing. Loss of CNTN2, a predicted protective modifier that encodes a GPI-anchored protein responsible for neuron/glial interactions, rescues loss of PIGA in the eye-based model, as we predict in the family. Further testing found that the loss of CNTN2 also rescues PIGA-CDG-specific phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. Using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in families may lead to therapeutic targets.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"572-582"},"PeriodicalIF":8.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing features affecting local ancestry inference performance in admixed populations.","authors":"Jessica Honorato-Mauer, Nirav N Shah, Adam X Maihofer, Clement C Zai, Sintia Belangero, Caroline M Nievergelt, Marcos Santoro, Elizabeth G Atkinson","doi":"10.1016/j.ajhg.2024.12.005","DOIUrl":"10.1016/j.ajhg.2024.12.005","url":null,"abstract":"<p><p>In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR). Simulating linkage-disequilibrium-informed admixed haplotypes under a variety of 2- and 3-way admixture models, we implemented a standard LAI pipeline, testing the impact of reference panel composition, DNA data type, demography, and software parameters to quantify ancestry-specific LAI accuracy. We observe that across all models, AMR tracts have notably reduced LAI accuracy as compared to EUR and AFR tracts, with true positive rate means for AMR ranging from 88% to 94%, EUR from 96% to 99%, and AFR from 98% to 99%. When LAI miscalls occurred, they most frequently erroneously called EUR ancestry in true AMR sites. Concerning reference panel curation, we find that using a reference panel well matched to the target population, even with a smaller sample size, was accurate and the most computationally efficient. Imputation did not harm LAI performance in our tests; rather, we observed that higher variant density improved accuracy. While directly responsive to admixed Latin American cohort compositions, these trends are broadly useful for informing best practices for LAI across admixed populations. Our findings reinforce the need for the inclusion of more underrepresented populations in sequencing efforts to improve reference panels.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"224-234"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.","authors":"Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar de la Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel","doi":"10.1016/j.ajhg.2024.12.012","DOIUrl":"10.1016/j.ajhg.2024.12.012","url":null,"abstract":"<p><p>BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and \"specificity residues\" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"394-413"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 unified framework for cell-type-specific eQTL prioritization by integrating bulk and scRNA-seq data.","authors":"Xinyi Yu, Xianghong Hu, Xiaomeng Wan, Zhiyong Zhang, Xiang Wan, Mingxuan Cai, Tianwei Yu, Jiashun Xiao","doi":"10.1016/j.ajhg.2024.12.018","DOIUrl":"10.1016/j.ajhg.2024.12.018","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) have identified numerous genetic variants associated with complex traits, yet the biological interpretation remains challenging, especially for variants in non-coding regions. Expression quantitative trait locus (eQTL) studies have linked these variations to gene expression, aiding in identifying genes involved in disease mechanisms. Traditional eQTL analyses using bulk RNA sequencing (bulk RNA-seq) provide tissue-level insights but suffer from signal loss and distortion due to unaddressed cellular heterogeneity. Recently, single-cell RNA-seq (scRNA-seq) has provided higher resolution, enabling cell-type-specific eQTL (ct-eQTL) analyses. However, these studies are limited by their smaller sample sizes and technical constraints. In this paper, we present a statistical framework, IBSEP, which integrates bulk RNA-seq and scRNA-seq data for enhanced ct-eQTL prioritization. Our method employs a hierarchical linear model to combine summary statistics from both data types, overcoming the limitations while leveraging the advantages associated with each technique. Through extensive simulations and real data analyses, including peripheral blood mononuclear cells and brain cortex datasets, IBSEP demonstrated superior performance in identifying ct-eQTLs compared to existing methods. Our approach unveils transcriptional regulatory mechanisms specific to cell types, offering deeper insights into the genetic basis of complex diseases at a cellular resolution.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"332-352"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}