HGG Advances最新文献

{"title":"Layers in the sand: The genetic imprint of migration, culture, and Indus craft in the Thar desert.","authors":"Rishabh Jain, Sachin M Rathod, Pankaj Jha, Deepika Jangir, Mohammed Faruq, Ganga Nath Jha, Mitali Mukerji","doi":"10.1016/j.xhgg.2026.100623","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100623","url":null,"abstract":"<p><p>The Thar Desert of Northwestern India, despite its harsh ecology, has sustained settlement of ancient crafts and pastoral communities. Their persistence provides a unique opportunity to study how migration, ecology, and culture have shaped genetic diversity. We analyzed genome-wide SNP data from 176 individuals across eight occupational communities along with global, Indian populations and diverse ancient-genomes. Population history, ancestral migration, population structure, demography, admixture, and founder-effects were elucidated using diverse population genetic statistical methods. The Thar groups occupy an intermediate position on the Indian North-South cline. Pastoralists and artisans (woodcarvers and Persian gold-embossers) with West Eurasian lineages, while potters and performers align with southern clines. Uniparental data confirmed heterogeneous Indian lineages. Gene-culture co-evolution was evident from the lactase-persistence allele being higher in pastoralists but lower in gold-embossers despite shared ancestry. Noteworthy, despite the desert environment, the populations retain a high frequency of the SLC24A5 allele associated with lighter skin-pigmentation in Europeans. Demographic analyses indicate an admixture of 60-80 Generation-before-present and strong founder-effects in certain groups, particularly tie-and-dye and Persian migrant-artisans ∼500-600 years ago. aDNA comparisons confirmed continuity with the Indus-periphery and historical South Asian populations. The genetic landscape of the Thar is a palimpsest shaped by successive layers of settlement, migration, and cultural continuity. By establishing the genomic baseline of Thar's craft and pastoral communities, this study shows how ecology and endogamy, along with population history, shape distinct genetic landscapes. These findings provide essential context for studying genetic risk, adaptation, and human resilience in extreme environments.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100623"},"PeriodicalIF":3.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome Sequencing for the Diagnosis of Rare Disorders: The Brazilian Rare Genomes Project.","authors":"Antonio Victor Campos Coelho, Rafael Sales de Albuquerque, Catarina Dos Santos Gomes, José Bandeira do Nascimento Junior, Gustavo Santos de Oliveira, Livia Maria Silva Moura, Luciana Souto Mofatto, Rafael Lucas Muniz Guedes, Rodrigo Araújo Sequeira Barreiro, Marcel Pinheiro Caraciolo, Ana Paula de Andrade Oliveira, Anne Caroline Barbosa Teixeira, Bruna Mascaro Cordeiro de Azevedo, Carolina Dias Carlos, Lucas Santos de Santana, Marina Cadena da Matta, Matheus Martinelli Lima, Nuria Bengala Zurro, Renata Yoshiko Yamada, Vivian Pedigone Cintra, Gabriela Pereira Campilongo, Gabriela Borges Cherulli Colichio, Renata Martins Ribeiro da Silva, Caio Robledo D'Angioli Costa Quaio, Carolina Araujo Moreno, Eduardo Perrone, Jéssica Grasiela Araújo Espolaor, Joana Rosa Marques Prota, José Ricardo Magliocco Ceroni, Kelin Chen, Luiza do Amaral Virmond, Marina de França Basto Silva, Michele Patricia Migliavacca, Renata Moldenhauer Minillo, Thiago Yoshinaga Tonholo Silva, Karla de Oliveira Pelegrino, Ana Luiza Garcia Cunha, Joziele de Souza Lima, Anete Sevciovic Grumach, Caio Parente Barbosa, Angelina Xavier Acosta, Paula Brito Corrêa, Denise Pontes Cavalcanti, Carlos Eduardo Steiner, Erlane Marques Ribeiro, Wallace William da Silva Meireles, Giselle Maria Araujo Felix Adjuto, Ida Vanessa Doederlein Schwartz, Têmis Maria Felix, Irma Cecilia Douglas Paes Barreto, Antonette Souto El Husny, Jussara Melo de Cerqueira Maia, Vera Maria Dantas, Lúcia Helena de Oliveira Cordeiro, Luiza Zagne Braz, Magda Maria Sales Carneiro Sampaio, Mara Lucia Schmitz Ferreira Santos, Marco Antonio Curiati, Maria Teresinha de Oliveira Cardoso, Maria Teresa Alves da Silva Rosa, Mariana Paes Leme Ferriani, Ester Silveira Ramos, Paula Teixeira Lyra, Raquel Tavares Boy da Silva, Anna Cândida Ximenes de Mendonça Sobreira, Tatiana Regia Suzana Amorim Boa Sorte, Melissa Rossi Calvão Dumas, Thaís Bomfim Teixeira, Vandré Cabral Gomes Carneiro, Patrícia Silva Mota, Tatiana Ferreira de Almeida, João Bosco Oliveira","doi":"10.1016/j.xhgg.2026.100624","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100624","url":null,"abstract":"<p><p>Genome Sequencing (GS) has emerged as a transformative tool in the diagnosis of rare diseases with complex phenotypes. This technology uncovers structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thus facilitating the understanding of the underlying genomic basis of human disorders. We enrolled 10305 patients with suspected rare diseases or hereditary cancer risk syndromes from 21 centers throughout Brazil. Their genomes were sequenced with short, paired-end reads, and diagnostic reports were provided for 9448 of these patients. The overall diagnostic yield was 35.6%, and 4.6% of all positive reports had GS-exclusive findings (e.g. short copy number variants overlapping fewer than three exons, deep intronic variants, short tandem repeats expansions, mitochondrial structural variants - usually not detected by other diagnostic tests such as exome sequencing). Preliminary analysis of transcriptome sequencing (TS) or long-read GS combined with the GS interpretation provided a small but welcome improvement in diagnostic yield (0.1% and 1.0% of positive reports, respectively). Almost 3200 variant/phenotype interpretations were submitted to ClinVar. GS is proving to be an invaluable resource for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. Therefore, GS has the potential to significantly enhance the precision of healthcare in genetically diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100624"},"PeriodicalIF":3.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction.","authors":"Sofia Douzgou Houge, Cecilie Bredrup, Ragnhild Wivestad Jansson, Ognjen Bojovic, Bayan M Aljamal, Maha Al-Otaibi, Astrid S Plomp, Mahdi M Motazacker, Maria M van Genderen, Anne Mellgren, Hisham Alkuraya, Omar Hikmat, Bjørn Ivar Haukanes, Fowzan S Alkuraya, Gunnar Douzgos Houge","doi":"10.1016/j.xhgg.2026.100622","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100622","url":null,"abstract":"<p><p>DSCAM occupies a 1 Mb locus in the original Down syndrome critical region on chromosome 21q22 and encodes a neuronal cell adhesion molecule of importance for brain and eye development. Singleton individuals, both born to first-cousin parents, with intellectual disability and homozygous DSCAM loss-of-function variants were reported in 2017 and in 2021, the latter also presenting with nystagmus and visual impairment. We present a cohort of 5 individuals, 4 new, including 2 sibling pairs with homozygosity or compound heterozygosity for predicted loss-of-function DSCAM variants. We identify a common clinical pattern of moderate to severe neurodevelopmental delay with poor language development, risk of focal seizures with onset in infancy, and nystagmus with poor vision. Electroretinography in two of the affected revealed cone pathway dysfunction with a b-wave pattern indicating main dysfunction at the level of the cone-associated bipolar cells of the central retina. Our electroclinical findings are in line with previous DSCAM knock-out-chicken and mice studies that evidenced disturbed horizontal and vertical patterning of the retina. Taken together, we delineate a rare syndromic form of recessive intellectual disability with a distinctive type of visual impairment.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100622"},"PeriodicalIF":3.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant effect predictors.","authors":"Aziz Zafar, Chao Hou, Naufa Amirani, Yufeng Shen","doi":"10.1016/j.xhgg.2026.100618","DOIUrl":"10.1016/j.xhgg.2026.100618","url":null,"abstract":"<p><p>Predictive models for missense variant pathogenicity offer little functional interpretation for intrinsically disordered regions (IDRs), since they mostly leverage conservation and coevolution across homologous sequences. In our study, we use molecular dynamics (MD) simulations to model biophysics of IDRs for improved interpretation of variant effects. We develop MDmis, a method that uses biophysical features extracted from MD simulations of IDRs to predict pathogenicity. We find that pathogenic variants in IDRs longer than 800 residues manifest differently, being strongly associated with a propensity for transient order and depleted solvent access, compared to those in IDRs <= 800 residues in length. Using MD simulations of proteins with single missense variants, we identify evidence for local structural changes, such as an increase in solvent accessible surface area, and global structural changes, such as increase in overall compaction, in IDRs >800aa. Lastly, MDmis, when combined with conservation information, can aid predictive accuracy, especially for pathogenic variants in IDRs >800aa. Overall, extracting information from MD simulations can help elucidate biophysical behaviors affected by pathogenic variants in IDRs and understand the drivers of predictive performance in different models.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100618"},"PeriodicalIF":3.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice.","authors":"Kassidy E Grover, Zoe R Cappel, Avery Volz, Evelin M Cotella, Kelly Smallwood, Christine A Berryhill, Kimaya R Raje, Austen A Fisher, Mary Claire T Casper, Diana Nardini, Tilat A Rizvi, Rosa M Salazar, Ashley Wooten, Michael T Williams, Charles V Vorhees, Lindsey E Romick, Kenneth D Greis, Yueh-Chiang Hu, Linde A Miles, Steven P Angus, Nancy Ratner, Carlos E Prada, K Nicole Weaver, Ronald R Waclaw, J Elliott Robinson","doi":"10.1016/j.xhgg.2026.100621","DOIUrl":"10.1016/j.xhgg.2026.100621","url":null,"abstract":"<p><p>Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called 'Rasopathies'. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100621"},"PeriodicalIF":3.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional and Computational Interrogation of the Juvenile Idiopathic Arthritis Risk Loci Identifies Candidate Risk-Driving SNPs and Target Genes in CD4+ T Cells.","authors":"Kaiyu Jiang, Emma K Haley, Gilad Barshad, Adam He, Anita Rogic, Edward Rice, Marc Sudman, Susan D Thompson, David A Murphy, Yao Fu, Lori Ponder, Maurice Davenport Munoz, Prashant Kolachala, Prahalad Sampath, Patrick M Gaffney, Charles G Danko, James N Jarvis","doi":"10.1016/j.xhgg.2026.100619","DOIUrl":"10.1016/j.xhgg.2026.100619","url":null,"abstract":"<p><p>GWAS have identified multiple genetic regions that confer risk for juvenile idiopathic arthritis (JIA). However, identifying the single nucleotide polymorphisms (SNPs) that drive disease risk has been impeded by the fact that the SNPs used to identify risk loci are in linkage disequilibrium (LD) with hundreds of other SNPs. Since the causal SNPs remain unknown, it is difficult to identify target genes and thus use genetic information to elucidate disease biology and inform patient care. We next used existing genotyping data from 3,939 children with JIA and 14,412 healthy controls to identify SNPs on JIA risk haplotypes that: present within open chromatin in multiple immune cell types and more common in children with JIA than the controls (p<0.05) in the genotyping data sets. We identified SNPs within cis-regulatory regions (CREs) using precision run-on sequencing data, and identified likely target genes using MicroC in both resting and activated CD4+ T cells. We identified 138 SNPs within the PROseq-identified CREs, and n=41 genes with which these CREs physically interacted. Data from GTEx and the Database of Immune Cell eQTLs (DICE) corroborated these analyses by showing allelic effects for SNPs within the CREs in the ERAP2/LNPEP and locus. We further corroborated IRF1 allelic effects using a luciferase reporter assay. Our findings significantly reduce the genomic search space for risk-driving variants and target genes and support the roles of IRF1, ERAP2 and LNPEP in driving risk for JIA.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100619"},"PeriodicalIF":3.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic utility of clinical genome reanalysis in rare pediatric disorders using long-read sequencing.","authors":"Elizabeth A Werren, Purva Vats, Gabriel E Rech, Michael Peracchio, Cameron King, Elizabeth J Charnysh, Ryan D Gorham, Peter A Audano, Peter N Robinson, Melissa A Kelly, Adam P Matson, Mark D Adams, Louisa Kalsner","doi":"10.1016/j.xhgg.2026.100620","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100620","url":null,"abstract":"<p><p>Over half of presumed genetic disease cases remain undiagnosed following short-read exome (SR-ES) or genome sequencing (SR-GS). Long-read genome sequencing (LR-GS) shows promise for uncovering etiologies missed by SR genetic testing, particularly structural variants (SVs). However, SV interpretation remains challenging due to limitations in call reliability, population allele frequency estimates, and functional impact prediction. To advance clinical LR-GS implementation, we analyzed the genomes of 19 children with suspected rare genetic conditions and prior negative or inconclusive clinical SR-GS/-ES and their parents using PacBio HiFi LR-GS. One additional family with limited DNA underwent Illumina SR-GS only, and 11 probands received SR-GS to complement small variant detection. LR-GS data were processed using phased-assembly and read-based variant calling pipelines validated on SV positive controls, while SR-GS data were processed with the Illumina DRAGEN pipeline. Variants were prioritized using phenotype-driven approaches. Diagnostic variants (likely pathogenic or pathogenic) were identified in 2/20 (10%) families, while an additional 5/20 (25%) harbored findings of uncertain diagnostic significance, including variants of uncertain significance (VUS) and variants in genes of uncertain significance (GUS). All reported variants were detected independently of LR-GS by research SR-GS or by reanalysis of prior clinical SR data. Several LR-GS SV candidates were excluded after population allele frequency filtering, underscoring its importance in clinical SV interpretation. Overall, the observed 10% increase in diagnostic yield was achievable through SR analysis alone, as LR-GS was not required to identify diagnostic variants in this cohort. Functional studies are needed to clarify the clinical relevance of uncertain findings.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100620"},"PeriodicalIF":3.6,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Von Hippel Lindau Gene Variants in an African American Cohort.","authors":"Yusra F Shao, Diana Duque, Abdul-Rahman Alloghbi, Bayan Al Share, Seongho Kim, Courtney Kokenakes, Elisabeth Heath","doi":"10.1016/j.xhgg.2026.100617","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100617","url":null,"abstract":"<p><p>Autosomal dominant (AD) pathogenic/likely pathogenic (P/LP) variants in Von-Hippel Lindau (VHL) gene cause VHL disease. We characterize VHL variants and disease phenotypes in Black/African American (AA) patients, a demographic not as thoroughly studied. Black/AA patients undergoing germline genetic testing at a CLIA certified commercial laboratory from November 2014 to March 2022 and carrying a P/LP AD VHL gene variant were identified. Personal and family histories were obtained from test requisition forms, and patients were categorized into VHL disease subtypes: Type 1, Type 2A, Type 2B, and Type 2C. Patients with a personal or family history of cancer but no lesions typical of VHL disease were categorized as \"Unclassified\". Patients with an incomplete personal or family history available were noted as \"Unknown\". Final analysis included 38 patients. Among the cohort's personal cancer history, hemangioblastoma and pheochromocytoma were most prevalent (16%). Among the cohort's family cancer history, renal cell carcinoma was most prevalent (8%). Type 1 was the most common VHL disease class recorded (34%). Substitution variants were most common (76%); p.Arg167Trp was the most common substitution (8%). Unique variants in Black/AA patients include p.Pro81Leu, p.Leu129Pro, p.Asp121Val, P.His110Profs*49, p.Arg82His. This dataset informs future research on VHL disease and treatment in Black/AA populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100617"},"PeriodicalIF":3.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCAFE: Estimating Case and Control Allele Frequencies from GWAS Summary Statistics.","authors":"Hayley R Stoneman, Hugo Lemus Gomez, Adelle Price, Christopher R Gignoux, Audrey E Hendricks","doi":"10.1016/j.xhgg.2026.100616","DOIUrl":"https://doi.org/10.1016/j.xhgg.2026.100616","url":null,"abstract":"<p><p>Genetic summary statistics can be used in a variety of analyses, such as causal inference, genetic correlation, and risk scores, to provide insights into the genetic architecture of conditions and traits. However, complete statistics are often not reported limiting the utility of this data. Indeed, many post-hoc analyses of diseases require case and control allele frequencies (AFs), which are not always published. Here, we present methods and software to derive case and control AFs from genome-wide association study (GWAS) summary statistics using the odds ratio, case and control sample sizes, and either the total (case and control aggregated) AF or standard error (SE). In simulations and real data, derivations of case and control AFs using total AF are highly accurate while using SE underestimates AFs when covariates were included in the GWAS. While estimating case and control AFs using the total AF is preferred due to its high accuracy, SE is more commonly available. Thus, we developed a bias adjustment using gnomAD AFs as a proxy for true AFs reducing bias when using SE. The methods and software provided here expand the utility of publicly available genetic summary statistics and promote the reusability of genomic data. The R package Case-Control Allele Frequency Estimation (CCAFE) is freely available on Bioconductor and GitHub.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100616"},"PeriodicalIF":3.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.","authors":"Matthieu Mantecon, Cerina Chhuon, Kevin Roger, Ida Chiara Guerrera, Christine Bole, Patrick Nitschke, Claire-Marie Dufeu-Bérat, Margaret Ashcroft, Robert W Taylor, Nathalie Boddaert, Agnès Rötig","doi":"10.1016/j.xhgg.2026.100615","DOIUrl":"10.1016/j.xhgg.2026.100615","url":null,"abstract":"<p><p>Mitochondrial disorders show remarkable clinical and genetic heterogeneity and result from variants in either mitochondrion- or nucleus-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects. Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100615"},"PeriodicalIF":3.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692638","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}