HGG Advances最新文献

Identification of technically challenging variants - whole genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases. 鉴定技术上具有挑战性的变异-全基因组测序提高了对罕见疾病临床高度怀疑的患者的诊断率。

IF 3.3

HGG Advances Pub Date : 2025-06-16 DOI: 10.1016/j.xhgg.2025.100469

Hau-Yee Ng, Wei Ma, Wai-Kei J Lam, Chak-Sing Lau, Ho-Ming Luk, Lisa W C Au, Shirley S W Cheng, Josephine S C Chong, Stephanie Ho, Becky M Ma, Shirley Y Y Pang, Annie T W Chu, Brian H Y Chung

{"title":"Identification of technically challenging variants - whole genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases.","authors":"Hau-Yee Ng, Wei Ma, Wai-Kei J Lam, Chak-Sing Lau, Ho-Ming Luk, Lisa W C Au, Shirley S W Cheng, Josephine S C Chong, Stephanie Ho, Becky M Ma, Shirley Y Y Pang, Annie T W Chu, Brian H Y Chung","doi":"10.1016/j.xhgg.2025.100469","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100469","url":null,"abstract":"The total burden of rare diseases is significant worldwide with over 300 million people being affected. Many of the rare diseases have both well-defined clinical phenotypes and established genetic causes. However, a remarkable proportion of patients with high clinical suspicion of a rare disease remain genetically undiagnosed and stuck in the diagnostic odyssey after having a cascade of conventional genetic tests. One of the major factors contributing to this is that many types of variants are technically intractable to whole exome sequencing (WES). In this study, the added diagnostic power of whole genome sequencing (WGS) for patients with clinically suspected rare diseases was assessed by detecting technically challenging variants. 3,169 cases from the Hong Kong Genome Project (HKGP) were reviewed and 322 patients having high clinical suspicion of a rare disorder with well-established genetic etiology were identified. Notably, 180 patients have performed at least one previous genetic test. Through a PCR-free short read WGS and a comprehensive in-house analytic pipeline, causative variants were found in 138 patients (138 of 322, 42.9%), in which 30 of them (30 of 138, 21.7%) are attributed to technically challenging variants. These included 6 variants in low coverage regions with PCR bias, 2 deep intronic variants, 2 repeat expansions, 19 structural variants, and 2 variants in genes with homologous pseudogene. The study demonstrated the indispensable diagnostic power of WGS in detecting technically challenging variants and the capability to serve as an all-in-one test for patients with high clinical suspicion of rare diseases.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100469"},"PeriodicalIF":3.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318174","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}

引用次数: 0

Long-Read Sequencing is Required for Precision Diagnosis of Incontinentia Pigmenti. 长读测序是精确诊断色素失禁所必需的。

IF 3.3

HGG Advances Pub Date : 2025-06-12 DOI: 10.1016/j.xhgg.2025.100468

Monica H Wojcik, Robin D Clark, Abdallah F Elias, Casie A Genetti, Jill A Madden, Dana Simpson, Linda Golkar, Miranda Pg Zalusky, Angela L Miller, Araceli Rodriguez, Joy Goffena, Camille A Dash, Nikhita Damaraju, Sophia B Gibson, Sophie Hr Storz, Zachary B Anderson, Jonas A Gustafson, Isabelle Thiffault, Emily G Farrow, Tomi Pastinen, Jasmine Lin, Jennifer Huang, Alan H Beggs, Pankaj B Agrawal, David T Miller, Danny E Miller

引用次数: 0

MED13L Pathogenic Missense Variants Impair Protein Stability and Interaction, Underlying Diverse Clinical Outcomes. MED13L致病性错义变异损害蛋白质稳定性和相互作用，潜在不同的临床结果。

IF 3.3

HGG Advances Pub Date : 2025-06-11 DOI: 10.1016/j.xhgg.2025.100467

Thomas Smol, Frédéric Frenois, Morgane Billotte, Roseline Caumes, Leonie A Menke, Amara Nassar-Sheikh Rashid, Caroline Thuillier, Didier Monté, Florence Petit, Alexis Verger, Jamal Ghoumid

{"title":"MED13L Pathogenic Missense Variants Impair Protein Stability and Interaction, Underlying Diverse Clinical Outcomes.","authors":"Thomas Smol, Frédéric Frenois, Morgane Billotte, Roseline Caumes, Leonie A Menke, Amara Nassar-Sheikh Rashid, Caroline Thuillier, Didier Monté, Florence Petit, Alexis Verger, Jamal Ghoumid","doi":"10.1016/j.xhgg.2025.100467","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100467","url":null,"abstract":"Heterozygous pathogenic variants in MED13L are associated with intellectual disability, developmental delay, and distinctive facial features. While nonsense and frameshift variants typically cause haploinsufficiency, resulting in a well-characterized clinical presentation, missense variants have been associated with a broader range of phenotypes, including epilepsy and severe motor delay. In this study, we investigated five pathogenic missense variants in MED13L - p.Pro866Leu, p.Pro869Ser, p.Cys1131Tyr, p.Gly1899Arg, and p.Thr2162Met - associated with different clinical severities. We identified significant reductions in protein stability across these variants, with some exhibiting aberrant cytoplasmic localization, suggesting disruptions in structural integrity and function. In particular, exon 15 variants (p.Pro866Leu and p.Pro869Ser) correlated with severe phenotypes, including epilepsy and severe motor impairment, whereas p.Gly1899Arg and p.Thr2162Met were associated with milder manifestations. 3D protein modeling suggested that these missense variants may disrupt MED13L's interaction with the CDK8 kinase module, leading to functional deficits. Our findings highlight different pathogenic mechanisms, ranging from protein instability to altered molecular interactions, that contribute to the clinical variability observed in MED13L-related disorders.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100467"},"PeriodicalIF":3.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276162","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}

引用次数: 0

The Impact of Genetic Ancestry on Survival Outcomes in Pediatric Rhabdomyosarcoma: A Report from the Children's Oncology Group. 遗传祖先对儿童横纹肌肉瘤生存结果的影响：一份来自儿童肿瘤学组的报告。

IF 3.3

HGG Advances Pub Date : 2025-06-09 DOI: 10.1016/j.xhgg.2025.100466

Ekene A Onwuka, Christina L Magyar, Bailey A Martin-Giacalone, Michael E Scheurer, Deborah A Marquez-Do, Mark Zobeck, Elizabeth G Atkinson, Erin R Rudzinski, Michael A Arnold, Donald A Barkauskas, David Hall, Javed Khan, Jack F Shern, Paul Scheet, Brian Crompton, Corinne M Linardic, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Chad D Huff, Melissa A Richard, Philip J Lupo

{"title":"The Impact of Genetic Ancestry on Survival Outcomes in Pediatric Rhabdomyosarcoma: A Report from the Children's Oncology Group.","authors":"Ekene A Onwuka, Christina L Magyar, Bailey A Martin-Giacalone, Michael E Scheurer, Deborah A Marquez-Do, Mark Zobeck, Elizabeth G Atkinson, Erin R Rudzinski, Michael A Arnold, Donald A Barkauskas, David Hall, Javed Khan, Jack F Shern, Paul Scheet, Brian Crompton, Corinne M Linardic, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Chad D Huff, Melissa A Richard, Philip J Lupo","doi":"10.1016/j.xhgg.2025.100466","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100466","url":null,"abstract":"Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were: 1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; and 2) overall survival (OS), defined as the time from study enrollment to death from any cause. Genetic ancestry was estimated using Grafpop software, and Cox regression assessed the association between genetic ancestry and EFS and OS, considering RMS overall, by fusion status, and histologic subtype. Covariates included sex, age at diagnosis, tumor stage, and histology, except during stratified analyses. In embryonal RMS and PAX3/7::FOXO1 fusion-negative RMS, individuals with South Asian or Asian-Pacific Islander ancestry showed worse EFS (HR: 2.06; 95% CI: 1.07-3.97; p = 0.03 and HR: 2.01; 95% CI: 1.07 - 3.76; p = 0.03, respectively) and OS (HR: 2.30; 95% CI: 1.09-4.84; p = 0.03 and HR: 2.33; 95% CI: 1.15 - 4.70; p = 0.020, respectively) compared to those with primarily European genetic ancestry. These findings suggest that genetic ancestry influences survival outcomes within RMS subtypes, and further understanding may improve precision medicine-based efforts.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100466"},"PeriodicalIF":3.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267447","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}

引用次数: 0

Meta-analysis of uveal melanoma genome-wide association studies identifies novel risk loci and population effect size heterogeneity. 葡萄膜黑色素瘤全基因组关联研究的荟萃分析确定了新的风险位点和群体效应大小异质性。

IF 3.3

HGG Advances Pub Date : 2025-06-09 DOI: 10.1016/j.xhgg.2025.100465

Georgia Mies, Noah L Tsao, Alexandre Houy, Sarah E Coupland, Helen Kalirai, Asta Försti, Kari Hemminki, Hauke Thomsen, Marc-Henri Stern, Carol L Shields, Scott M Damrauer, Katheryn G Ewens, Arupa Ganguly, Iain Mathieson

{"title":"Meta-analysis of uveal melanoma genome-wide association studies identifies novel risk loci and population effect size heterogeneity.","authors":"Georgia Mies, Noah L Tsao, Alexandre Houy, Sarah E Coupland, Helen Kalirai, Asta Försti, Kari Hemminki, Hauke Thomsen, Marc-Henri Stern, Carol L Shields, Scott M Damrauer, Katheryn G Ewens, Arupa Ganguly, Iain Mathieson","doi":"10.1016/j.xhgg.2025.100465","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100465","url":null,"abstract":"Uveal melanoma (UM) is a rare but frequently metastasizing cancer. Genome-wide association studies have identified three common genome-wide significant germline risk loci. Here, we perform a genome-wide association study on 401 new cases and conduct a meta-analysis with three independent previously published cohorts for a total sample size of 2,426 cases. We confirm the three previously identified risk loci and identify four additional genome-wide significant loci. We find that eye pigmentation decreasing variants are systematically associated with increased UM risk, and that selection for lighter pigmentation in the past 5000 years explains about 73% of the difference in UM incidence between Northern and Southern Europe. We find evidence of effect size heterogeneity at significant loci across cohorts, in particular, a weaker association between eye pigmentation and UM in a Finnish cohort. Finally, we confirm differential effect sizes between uveal melanoma cases with and without loss of chromosome 3, the major determinant of metastatic risk. Our study identifies novel germline risk factors for UM and highlights genetic and environmental heterogeneity in its etiology.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100465"},"PeriodicalIF":3.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267446","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}

引用次数: 0

Expanding implementation of pediatric whole genome sequencing: insights from SeqFirst providers to inform equitable access to a precise genetic diagnosis. 扩大儿科全基因组测序的实施：来自SeqFirst提供者的见解，为公平获得精确的遗传诊断提供信息。

IF 3.3

HGG Advances Pub Date : 2025-06-03 DOI: 10.1016/j.xhgg.2025.100464

Joon-Ho Yu, Katherine E MacDuffie, Olivia Sommerland, Tesla Theoryn, Priyanka Murali, Kailyn Anderson, Megan Sikes, Lukas Kruidenier, Heidi Gildersleeve, Abbey Scott, Kati J Buckingham, Kirsty McWalter, Paul Kruszka, Alexandra Keefe, Danny E Miller, Jessica X Chong, David L Veenstra, Katrina M Dipple, Tara Wenger, Dan Doherty, Michael J Bamshad

{"title":"Expanding implementation of pediatric whole genome sequencing: insights from SeqFirst providers to inform equitable access to a precise genetic diagnosis.","authors":"Joon-Ho Yu, Katherine E MacDuffie, Olivia Sommerland, Tesla Theoryn, Priyanka Murali, Kailyn Anderson, Megan Sikes, Lukas Kruidenier, Heidi Gildersleeve, Abbey Scott, Kati J Buckingham, Kirsty McWalter, Paul Kruszka, Alexandra Keefe, Danny E Miller, Jessica X Chong, David L Veenstra, Katrina M Dipple, Tara Wenger, Dan Doherty, Michael J Bamshad","doi":"10.1016/j.xhgg.2025.100464","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100464","url":null,"abstract":"Whole genome sequencing (WGS) as a diagnostic test offers children suspected of having a rare genetic condition and their families the best direct path toward securing a precise genetic diagnosis (PrGD). Yet, limited supply and inequitable access to genetic services are impediments to realizing the benefits of a PrGD. Such access disparities might be due to a range of structural and social determinants that manifest in interactions, or the lack thereof, between families, providers, and institutions. Semi-structured key informant interviews were conducted with neonatologists and neurodevelopmental clinic providers (NDV providers) who referred families to the SeqFirst study to identify barriers and inform strategies to improve equitable access to a PrGD via WGS. Overall, neonatologists and NDV providers were enthusiastic about offering WGS to their patients and families despite different contexts of medical care. Providers cited several considerations that influenced their introduction of WGS and genetic testing to families including their perceptions of families' capacity, readiness, and distrust, and establishment of sufficient provider-family rapport. These considerations influenced providers' timing and introduction of genetic testing and WGS to families. Together, these findings suggest that providers' perceptions of families may result in delayed introduction of WGS.‬ Despite enthusiasm for early WGS across medical subspecialties, providers' perceptions of families and their social contexts highlight both challenges and opportunities in the implementation of WGS to promote and maximize equitable access.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100464"},"PeriodicalIF":3.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226965","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}

引用次数: 0

Transcriptomic signatures of rare variant impacts across sex and the X chromosome. 罕见变异跨性别和x染色体影响的转录组学特征。

IF 3.3

HGG Advances Pub Date : 2025-05-31 DOI: 10.1016/j.xhgg.2025.100463

Rachel A Ungar, Taibo Li, Nikolai G Vetr, Nicole Ersaro, Alexis Battle, Stephen B Montgomery

{"title":"Transcriptomic signatures of rare variant impacts across sex and the X chromosome.","authors":"Rachel A Ungar, Taibo Li, Nikolai G Vetr, Nicole Ersaro, Alexis Battle, Stephen B Montgomery","doi":"10.1016/j.xhgg.2025.100463","DOIUrl":"10.1016/j.xhgg.2025.100463","url":null,"abstract":"The human X chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X chromosome is understudied. To investigate functional rare variants on the X chromosome, we use observations of outlier gene expression from Genotype Tissue Expression consortium data. We show that outlier genes are enriched for having nearby rare variants on the X chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 733 rare variants in 450 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Overall, we observed more within-sex variation than between-sex variation. Combined, our study investigates functional rare variants on the X chromosome, and further details how sex stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100463"},"PeriodicalIF":3.3,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200159","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}

引用次数: 0

Breaking barriers in rare disease research: The RARE-X Open Science Data Challenge as a model for collaborative innovation and community partnership. 打破罕见病研究的障碍：Rare - x开放科学数据挑战作为协作创新和社区伙伴关系的模式。

IF 3.3

HGG Advances Pub Date : 2025-05-30 DOI: 10.1016/j.xhgg.2025.100462

Karmen Trzupek, Ravi Bhargava, Cynthia Kuan, Fanny Sie, Vanessa Vogel-Farley, Katelyn Hobbs, Verena Chung, Maria Diaz, Charlene Son-Rigby, Joseph Geraci, Jacob Albrecht

引用次数: 0

Clinical features and molecular mechanisms of RP1L1 variants causing occult macular dystrophy. RP1L1变异引起隐匿性黄斑营养不良的临床特征及分子机制。

IF 3.3

HGG Advances Pub Date : 2025-05-30 DOI: 10.1016/j.xhgg.2025.100461

Yang Pan, Daisuke Iejima, Kazutoshi Yoshitake, Kazushige Tsunoda, Takeshi Iwata

{"title":"Clinical features and molecular mechanisms of RP1L1 variants causing occult macular dystrophy.","authors":"Yang Pan, Daisuke Iejima, Kazutoshi Yoshitake, Kazushige Tsunoda, Takeshi Iwata","doi":"10.1016/j.xhgg.2025.100461","DOIUrl":"10.1016/j.xhgg.2025.100461","url":null,"abstract":"Occult macular dystrophy (OMD) is an inherited retinopathy characterized by progressive bilateral vision loss despite normal findings on fundoscopic examination, fluorescein angiography, and full-field electroretinography. Its pathogenesis remains unknown, and no treatments are available. Here, we performed whole-exome sequencing on 133 samples from 78 OMD pedigrees to identify pathogenic variants, using filters for minor allele frequency, function prediction, and retinal expression. We identified the RP1L1 c.133C>T, p.Arg45Trp (R45W) mutation as the sole pathogenic variant in two families with dominantly inherited OMD. Additionally, we discovered five other potentially pathogenic RP1L1 variants. Together, these six variants accounted for 33.33% of pedigrees, with R45W being the most prevalent, at 16.6%. The R45W mutation correlated with earlier onset, more severe clinical phenotypes, and abnormal intracellular localization rather than altered expression levels. R45W disrupted the intracellular localization of RP1L1 and RP1, compromising cell viability. In induced photoreceptor-like cells derived from OMD patients carrying R45W, we observed downregulation of the long noncoding RNA MEG3 and the PI3K/Akt pathway, alongside upregulation of extracellular matrix organization. These findings validate the etiologic role of RP1L1 and offer insights into the pathogenesis of OMD, thereby facilitating future research and therapeutic development.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100461"},"PeriodicalIF":3.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226964","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}

引用次数: 0

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies. brca1 /2阴性家族遗传性乳腺癌和卵巢癌的靶向测序揭示了复杂的遗传结构和表型。

IF 3.3

HGG Advances Pub Date : 2025-05-23 DOI: 10.1016/j.xhgg.2025.100453

Jocelyn N Plowman, Evanjalina J Matoy, Lavanya V Uppala, Samantha B Draves, Cynthia J Watson, Bridget A Sefranek, Mark L Stacey, Samuel P Anderson, Michael A Belshan, Elizabeth E Blue, Chad D Huff, Yusi Fu, Holly A F Stessman

引用次数: 0