HGG Advances最新文献

{"title":"Trio-based GWAS reveals loci associated with different forms of isolated cleft lip.","authors":"Noah Herrick, Zeynep Erdogan-Yildirim, Myoung Keun Lee, Sarah W Curtis, Seth Berke, Grace C Brewer, Toby McHenry, Ahmed M El Sergani, Joel Anderton, Nandita Mukhopadhyay, Jenna C Carlson, Terri Beaty, Azeez Butali, Carmen J Buxo-Martinez, Jacqueline T Hecht, Eric C Liao, Lina M Moreno Uribe, Carmencita D Padilla, George Wehby, Eleanor Feingold, Jeffrey C Murray, Ingo Ruczinski, Elizabeth J Leslie-Clarkson, Seth M Weinberg, John R Shaffer, Mary L Marazita","doi":"10.1016/j.xhgg.2026.100672","DOIUrl":"10.1016/j.xhgg.2026.100672","url":null,"abstract":"<p><p>Orofacial clefts (OFCs) are the most common craniofacial birth defect and comprise a diverse group of traits with complex and heterogeneous etiologies. Genetic studies of OFCs typically approach this diversity by stratifying cases into broad diagnostic classes, including cleft lip (CL), cleft palate (CP), and cleft lip with palate (CLP). Although this strategy has yielded important insights into OFC risk, it ignores the phenotypic heterogeneity within each subtype. CL exhibits marked phenotypic variability, involving differences in alveolar involvement, laterality, and sidedness that may reflect distinct etiologies. Given this phenotypic diversity within CL, we assembled a multi-ancestry cohort of 837 nonsyndromic CL case-parent trios with whole-genome sequencing and detailed phenotyping. We performed genome-wide association scans (GWASs) via transmission disequilibrium tests for CL overall and for 14 CL subtypes defined by involvement of the alveolus (with and without), laterality (uni- and bilateral), and sidedness (left and right). We identified four genome-wide significant loci. Two loci, IRF6 and 8q24.21, were both detected in the overall CL GWAS. PLCB1/PLCB4 and MAFB were detected in GWASs of alveolar cleft involvement and CL left-sidedness, respectively. These subtype-specific associations were followed by case-only comparisons that reflect the presence or absence of alveolus cleft or left-sided bias of CL to confirm the specificity of the association signal to the particular subtype. Our results provide evidence of within-class CL-subtype-specific genetic links for loci previously discussed in the context of primary OFC classes and demonstrate the value of granular OFC subtype characterization to capture trait-specific associations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100672"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148931409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A lethal form of ASCC3 disease: Severe global developmental delay, axial hypotonia, hypoplasia of corpus callosum, hypothyroidism, and micropenis.","authors":"Ginat Narkis, Vadim Dolgin, Sufa Sued-Hendrickson, Juman Zahran, Bibi Kanengisser-Pines, Gil Smooha-Schechter, Lior Carmon, Zamir Shorer, Analia Michaelovsky, Ohad S Birk","doi":"10.1016/j.xhgg.2026.100637","DOIUrl":"10.1016/j.xhgg.2026.100637","url":null,"abstract":"<p><p>Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) encodes a DNA helicase that is pivotal in transcriptional regulation, DNA damage response, and ribosomal quality control. Bi-allelic ASCC3 variants have been recently associated with a wide spectrum of non-lethal neuromuscular and neurodevelopmental disorders, with no consistent brain malformations or endocrine dysfunction. We describe a severe lethal form of ASCC3 disease: eight individuals of three consanguineous Bedouin families presented with a consistent phenotype of severe global developmental delay, axial hypotonia, and hypoplasia of the corpus callosum, lethal in infancy. Shared dysmorphic features included narrow palpebral fissures, a sunken flat nasal bridge with a short nasal tip and anteverted nares, and low-set ears. Congenital hypothyroidism was evident in most affected individuals, and all males had micropenis/cryptorchidism. Linkage analysis identified a chromosome 6q16.3 locus segregating within the families consistent with autosomal recessive inheritance (maximum multipoint LOD score: 3.1). Whole-exome sequencing followed by segregation analysis identified within this locus a single disease-associated variant: ASCC3 c.3061T>A (GenBank: NM_006828.4) (p.Phe1021Ile). The phenotype, consistent across all affected individuals, significantly broadens the phenotypic spectrum of ASCC3-related disorders, with unique dysmorphism, previously unreported agenesis of the corpus callosum, micropenis/cryptorchidism, congenital hypothyroidism (possibly relevant to ASCC3's pituitary and thyroid expression and its thyroid hormone receptor interacting protein 4 [TRIP4] interaction), and early lethality.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100637"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148309596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pseudotime-dependent TWAS framework identifies disease genes along cell developmental paths.","authors":"Rui Cao, Chunlin Li, Erjia Cui, Logan Spector, Andrew Raduski, Nathan Anderson, Weihua Guan, Peter Gordon, Cindy Im, Tianzhong Yang","doi":"10.1016/j.xhgg.2026.100634","DOIUrl":"10.1016/j.xhgg.2026.100634","url":null,"abstract":"<p><p>Transcriptome-wide association studies (TWASs) link genes to disease risk by integrating gene expression with genome-wide association study (GWAS) data. The growing availability of single-cell expression data offers the opportunity to dissect these associations at finer cellular resolution and uncover effects masked in bulk TWAS analyses. Existing single-cell TWAS methods often map associations to discrete cell types, potentially overlooking the continuous nature of cellular processes and misidentifying the causal cell stages where genes exert their effects. To address this limitation, we developed the pseudotime-dependent TWAS (pt-TWAS), a framework that models gene expression as a continuous function of pseudotime to capture dynamic gene effects along developmental trajectories. By flexibly modeling and utilizing shared genetic effects across cell stages, this approach achieved higher statistical power than existing single-cell TWAS methods in our extensive simulations. pt-TWAS further enables identification of causal cell stages underlying disease risk by constructing confidence bands for gene effect curves. Applied to a GWAS of B cell acute lymphoblastic leukemia using single-cell data from OneK1K, pt-TWASs replicated known risk genes and pinpointed their relevant cell stages, demonstrating its utility for revealing fine-grained, cell-stage-specific genetic mechanisms. An R package implementing pt-TWASs is available on GitHub.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100634"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13400862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148309619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The AP5B1 p.Leu785Pro variant is a frequent cause of late-onset macular dystrophy with variable extraocular manifestations.","authors":"Petra Liskova, Lubica Dudakova, Karolina Kaminska, Laura Kühlewein, Stefanida Shliaga, Rina Leibu, Miriam Ehrenberg, Dinah Zur, Jana Zernant, Miriam Bauwens, Gavin Arno, Isabelle Müller, Focke Ziemssen, Viktoria Bothe, Francesca Cancellieri, Julie De Zaeytijd, Pascale Mazzola, Winston Lee, Bohdan Kousal, Marie Vajter, L Ingeborgh van den Born, Anton Sonntag, Yoeri van Leeuwen, Dzenita Smailhodzic, Caroline C W Klaver, Tobias B Haack, Bernd Wissinger, Andrew R Webster, Lonneke Haer-Wigman, Siying Lin, Moreno Menghini, Konrad Platzer, Elfride De Baere, Rando Allikmets, Carlo Rivolta, Susanne Roosing, Susanne Kohl, Tamar Ben-Yosef, Mathieu Quinodoz","doi":"10.1016/j.xhgg.2026.100659","DOIUrl":"10.1016/j.xhgg.2026.100659","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) represent a large group of genetically heterogeneous disorders that often cause progressive visual loss. The fifth adaptor protein (AP-5) complex, which contributes to endolysosomal trafficking and lysosomal homeostasis, has previously been implicated in neurodegenerative syndromes, and more recently, bi-allelic variants in three of its subunits were found in families with macular dystrophy, including four with variants in AP5B1. Here, we describe 22 affected individuals from 20 families with AP5B1-associated IRD, all carrying the recurrent missense variant c.2354T>C (GenBank: NM_138368.5) (p.Leu785Pro), either in the homozygous state (16 families) or in trans with another rare heterozygous AP5B1 missense or loss-of-function variant. Five families were of Ashkenazi Jewish ancestry and 15 families of European ancestry. Clinically, affected individuals presented with a predominantly late-onset macular dystrophy that frequently progressed to cone-rod degeneration. Characteristic retinal findings included foveal sparing, early peripapillary involvement, and a reticular pattern best observed by fundus autofluorescence imaging in the mid- or peripheral retina. The typical presenting symptom was decreased visual acuity. Age at onset ranged from 27 to 74 years, with most individuals becoming symptomatic after the fifth decade of life. Some individuals also presented with extraocular manifestations, most notably hearing loss, which was reported in 8 affected individuals. These findings further support AP5B1 as a cause of macular dystrophy, identify p.Leu785Pro as a relatively frequent pathogenic allele in individuals of European and Ashkenazi Jewish ancestry, and expand the associated phenotypic spectrum to include both isolated macular dystrophy and possible syndromic presentations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100659"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13524567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study of untargeted plasma metabolomic profiles identifies host genetic regulation in people with HIV.","authors":"Mariam Ait Oumelloul, Adriaan van der Graaf, Simon Tang, Christian W Thorball, Marco Labarile, Ali Saadat, Valeriia Timonina, Isabella C Schöpf, Gilles Wandeler, Johannes Nemeth, Matthias Cavassini, Alexandra Calmy, Patrick Schmid, Marcel Stöckle, Luigia Elzi, Nicola Zamboni, Roger D Kouyos, Philip E Tarr, Jacques Fellay","doi":"10.1016/j.xhgg.2026.100635","DOIUrl":"10.1016/j.xhgg.2026.100635","url":null,"abstract":"<p><p>People with human immunodeficiency virus (PWH) exhibit accelerated aging and a higher prevalence of aging-related conditions, despite effective antiretroviral therapy. The biological mechanisms involved remain incompletely understood. Integrating genomic and metabolomic profiling may help uncover genes and pathways contributing to aging-related disease in this population. Using a genome-wide association study framework and untargeted metabolomic profiling, we searched for associations between human genetic variants and the plasma concentrations of 1,930 putative metabolites in 1,244 individuals enrolled in the Swiss HIV Cohort Study. We performed an expression quantitative trait locus (eQTL) colocalization analysis to explore biological links between genetic variants and metabolites and used Mendelian randomization to search for causal relationships between metabolites and aging-related diseases. We identified 27 metabolites significantly associated with 12 genetic loci, including genes encoding the metabolic enzymes NAT8 and FUT2; 10 associations had been previously reported in general-population studies, of which eight were replicated in our analysis. The colocalization analyses provided evidence for a large overlap between genetic regulation of mRNA expression and metabolite levels, while Mendelian randomization suggested several causal effects. Our study uncovered genetic-metabolic associations observed in PWH and explored their biological relevance. These findings highlight the potential of integrated multi-omics profiling to deepen mechanistic understanding and inform future precision approaches to comorbidity management in this population.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100635"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148273050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Underrepresented voices in a Colorado Biobank: Perspectives from focus groups on motivations, return of results, and data sharing.","authors":"Carissa A Sherman, Betzaida L Maldonado, Lucas O Rozell, Sarah D Slack, Isabella E Eaton, Doreen E Martinez, Randi K Johnson, Katrina G Claw","doi":"10.1016/j.xhgg.2026.100660","DOIUrl":"10.1016/j.xhgg.2026.100660","url":null,"abstract":"<p><p>Most participants in large cohorts, such as biobanks, are of European descent. This lack of representation has been an ongoing challenge in genomic research. Understanding the perspectives on genomics research and participation in biobanks of historically underrepresented populations could provide insight into ways to better engage with these groups. We conducted a series of virtual and in-person focus groups with individuals who self-identified as American Indian or Alaska Native (AI/AN), African American/Black (AA/B), or Hispanic/Latino (H/L) and who were enrolled in the Colorado Center for Personalized Medicine (CCPM) biobank. The focus group discussions were centered on participant experiences, including but not limited to their motivations, return of results, and data sharing. There was a total of 23 participants across the six focus groups. The majority of participants identified as AI/AN (60.9%), followed by H/L (39.1%), and AA/B (21.7%); many participants identified with multiple race/ethnicities. The motivations for participating in the biobank included the potential to advance science and health, the potential for return of results, to learn more about one's ancestry, and a few indicated that they were interested in helping the biobank be more representative of all populations. Notably, many expressed positive feedback of the focus groups and felt that their views were valued, illustrating the importance of community-centered work. Our findings can be used to guide recruitment and engagement of biobank participants, especially from diverse backgrounds, contributing to enhanced partnerships advancing knowledge and healthcare.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100660"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression.","authors":"Hans M Dalton, Elizabeth M Brydon, Tiffany S Chan, Katie G Owings, Mandi M L Wild, Naomi J Young, Clement Y Chow","doi":"10.1016/j.xhgg.2026.100666","DOIUrl":"10.1016/j.xhgg.2026.100666","url":null,"abstract":"<p><p>The cell must defend against various stressors from internal and external sources that disrupt cell homeostasis. The integrated stress response (ISR) is a highly conserved pathway that helps restore this homeostasis through upregulating the transcription factor ATF4. Despite its importance to cell health and human disease, ATF4 has several duplications in humans that have not been characterized. Here, we characterize four retroduplications (retrocopies) of ATF4 in humans. Evolutionary analysis demonstrates that these retrocopies are present and intact in many primate species over the past 37 million years, including several independent copies. We also find evidence of non-neutral evolution among primates. Human ATF4 retrocopies show basal transcription in healthy, unstressed cells and can be upregulated by the ISR. When translated in human cells, ATF4 retrocopy proteins are regulated by the proteasome in the same way as the parent ATF4 protein. Remarkably, each retrocopy can also alter the expression of several canonical ATF4 target genes, demonstrating that they can impact ISR-ATF4 stress signaling. Overall, ATF4 retrocopies are conserved, biologically functional, and should be considered in future studies of the ISR and ATF4.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100666"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148833224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considering social risk alongside genetic risk for bipolar disorder in the All of Us Research Program.","authors":"Rachel R Sharp, Micah R Hysong, Robert G Mealer, Laura M Raffield, LáShauntá Glover, Michael I Love","doi":"10.1016/j.xhgg.2026.100665","DOIUrl":"10.1016/j.xhgg.2026.100665","url":null,"abstract":"<p><p>Polygenic risk scores (PRSs) have shown increasing utility for risk stratification across complex diseases, but for psychiatric disorders such as bipolar disorder (BD), current PRSs explain only a fraction of disorder liability (∼1%-9%), with predictive performance further diminished in non-European populations and electronic health record (EHR)-linked biobanks. To explore the potential of integrating social and environmental risk factors alongside genetic liability to improve risk characterization, we evaluated the relationship between a PRS for BD (PRS_BD) and six social risk measures-perceived stress, discrimination in medical settings, neighborhood social cohesion, perceived neighborhood disorder, cost-related medication nonadherence, and adverse childhood experiences (ACEs)-to BD case status in 115,275 participants (7,000 affected individuals and 108,275 control subjects) from the All of Us Research Program. PRS_BD was associated with BD case status across ancestry groups, though liability-scale variance explained was attenuated relative to what has been reported for curated research cohorts (R² = 1.86% in European, 0.60% in African, and 1.65% in Latino/Admixed American ancestries). Each social risk factor tested exhibited a larger effect size than PRS_BD, with perceived stress (odds ratio [OR] = 2.05 per SD) and ACEs (OR = 2.68 for ≥4 ACEs) demonstrating the strongest associations. Individuals in the lowest genetic risk decile with high social burden exhibited BD prevalence comparable to or exceeding that in the highest genetic risk decile with low social burden. These findings demonstrate the substantial explanatory power of social risk factors and support the development of integrated genetic-social risk frameworks for more accurate and equitable characterization of psychiatric risk.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100665"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of genetic variants associated with idiopathic inflammatory myopathies via cross-trait analysis with B cell lymphomas.","authors":"Weng Ian Che, James N Jarvis, Anton Öberg Sysojev, Catherine Zhu, Karina Patasova, Karin E Smedby, Ingrid E Lundberg, Helga Westerlind, Janine A Lamb, Marie Holmqvist","doi":"10.1016/j.xhgg.2026.100658","DOIUrl":"10.1016/j.xhgg.2026.100658","url":null,"abstract":"<p><p>The genetic architecture of idiopathic inflammatory myopathies (IIMs) remains incompletely defined. When increasing sample size is not feasible, cross-trait analysis of genetically correlated diseases offers an effective strategy for discovering risk loci. Using summary statistics of IIM and B cell lymphoma subtypes, we applied conditional false discovery rate (condFDR) and multi-trait analysis of genome-wide association studies (GWASs) (MTAG) to detect genetic associations with IIM risk. Single-nucleotide polymorphisms (SNPs) outside the human leukocyte antigen (HLA) region meeting significance thresholds (condFDR < 0.01 or p <5 × 10^-8 for MTAG) were clumped and subjected to both functional annotation in FUMA and Gene Ontology (GO) biological process enrichment analysis using clusterProfiler. We identified six previously unreported loci, including three associated with dermatomyositis (chr12:58674304T>C, chr13:110799415C>T, and chr17:38103285G>A (hg19)) and three associated with polymyositis (PM) (chr4:971496T>C, chr6:396321C>T, and chr6:32650631C>A). All non-HLA loci act as expression quantitative trait loci (eQTL) or localize within enhancer regions. Notably, these include cis-eQTLs for known IIM risk-associated genes (GSDMB, DGKQ, SLC26A1, and IDUA) as well as genes implicated in synaptic vesicle cycle (SVC) pathways, immune regulation (IKZF3, ORMDL3, IRF4, DUSP22, and SPON2), protein homeostasis (ATP23 and PSMD3), lipid metabolism (PGAP3, ORMDL3, STARD3, and DGKQ), and myopathy (COL4A1). GO analysis revealed significance for SVC pathways in PM (FDR < 0.05). These findings advance our understanding of IIM pathogenesis from a genetic perspective and highlight candidate regulatory variants for further mechanistic investigation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100658"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148585376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between genomic architecture alterations and GDF6 regulation: A candidate mechanism in Nablus mask-like facial syndrome.","authors":"Alexandru Marian Bologa, Luiza Dimos, Anca Gabriela Pavel, Maria Stratan, Petruța Elisabeta Bână, Danae Stambouli, Iustin Butnariuc, Radu-Alexandru Truică, Ina-Ofelia Focşa, Vasilica Plăiașu, Andreea Țuțulan-Cuniță","doi":"10.1016/j.xhgg.2026.100640","DOIUrl":"10.1016/j.xhgg.2026.100640","url":null,"abstract":"<p><p>Nablus mask-like facial syndrome (NMLFS) is a very rare disorder associated with 8q22.1q22 microdeletions and characterized by a distinctive facial phenotype and variable neurological, cardiological, and genital anomalies. However, not all affected individuals with overlapping deletions present the mask-like phenotype, thus suggesting the involvement of an additional regulatory mechanism. Here, we perform a comparative analysis of previously reported affected individuals (n = 30) with deletions in the 8q21q22 region, stratified by the presence or absence of the NMLFS phenotype, and including an affected individual from Romania with an 8q21.13q22.1 microdeletion. We investigated the 3D genomic architecture, focusing on topologically associating domains (TADs) and regulatory elements, and identified a recurrent pattern of candidate TAD fusion significantly associated with NMLFS. This configuration brings a cluster of ultra-conserved non-coding elements (UCNEs) in the proximity of GDF6, a known regulator of craniofacial development. Thus, we propose a mechanism involving TAD fusion and enhancer hijacking affecting the candidate gene GDF6 that may underlie the facial anomaly and provide insight into the variable expressivity in 8q22.1 microdeletion syndrome.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100640"},"PeriodicalIF":3.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}