HGG Advances最新文献_第4页

Homozygous variants in EIF3K associated with neurodevelopmental delay, microcephaly, and growth retardation. EIF3K的纯合子变异与神经发育迟缓、小头畸形和生长迟缓有关。

IF 3.3

HGG Advances Pub Date : 2025-04-11 DOI: 10.1016/j.xhgg.2025.100438

Bobbi McGivern, Tess Holling, Maria J Guillen Sacoto, Hákon Gudbjartsson, Ibrahim M Abdelrazek, Malik Alawi, Yan Bai, Olaf Bodamer, Amy Crunk, Amy E Dameron, Lisa M Dyer, Lindsay B Henderson, Mira Irons, Kerstin Kutsche, Caroline McGowan, Kristin G Monaghan, Kaitlyn O'Connor, Asma Rashid, Olivia L Redlich, Adi Reich, Christopher Simotas, Sara Welner, Ingrid M Wentzensen

{"title":"Homozygous variants in EIF3K associated with neurodevelopmental delay, microcephaly, and growth retardation.","authors":"Bobbi McGivern, Tess Holling, Maria J Guillen Sacoto, Hákon Gudbjartsson, Ibrahim M Abdelrazek, Malik Alawi, Yan Bai, Olaf Bodamer, Amy Crunk, Amy E Dameron, Lisa M Dyer, Lindsay B Henderson, Mira Irons, Kerstin Kutsche, Caroline McGowan, Kristin G Monaghan, Kaitlyn O'Connor, Asma Rashid, Olivia L Redlich, Adi Reich, Christopher Simotas, Sara Welner, Ingrid M Wentzensen","doi":"10.1016/j.xhgg.2025.100438","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100438","url":null,"abstract":"We report two rare homozygous variants, including a recurrent missense and intronic variant, in the EIF3K gene in four unrelated individuals with global developmental delay, microcephaly, proportionate short stature, dysmorphic craniofacial features, digit flexion deformities, and the cardiac anomaly, patent ductus arteriosus. Three individuals, who were all of Puerto Rican descent, were homozygous for the NM_013234.3:c.128A>G; p.(Asp43Gly) variant in EIF3K and homozygous for a missense variant in SYNE4 (NM_001039876.2:c.355C>T; p.(Arg119Trp)). SYNE4 is associated with autosomal recessive bilateral sensorineural hearing loss, which was also reported in these probands. Analysis of our dataset confirmed these EIF3K and SYNE4 variants were in linkage disequilibrium in affected individuals, suggesting a possible common ancestor and founder event. A fourth individual from Egypt harbored the homozygous intronic variant c.355-13A>G in EIF3K, which segregated with the phenotype in the family and led to aberrant splicing of EIF3K pre-mRNAs, as shown by insertion of 12 intronic base pairs, skipping of 2 exons, and significantly reduced EIF3K protein levels in skin fibroblasts. Through genetic and functional approaches, we suggest that biallelic EIF3K variants are associated with an autosomal recessive syndromic neurodevelopmental disorder with growth retardation, microcephaly, congenital heart defect, and other anomalies.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":"6 3","pages":"100438"},"PeriodicalIF":3.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044157","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}

引用次数: 0

Response to Karp-Tatham et al. 对致编辑的信的回应：经典HLA基因与无症状SARS-CoV-2感染之间缺乏关联。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-01-17 DOI: 10.1016/j.xhgg.2025.100407

Astrid Marchal, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze

引用次数: 0

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection. 致编辑的信：经典HLA基因与无症状SARS-CoV-2感染之间缺乏关联。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2024-11-02 DOI: 10.1016/j.xhgg.2024.100382

Eleanor Karp-Tatham, Callum R O'Neill, Julian C Knight, Alexander J Mentzer, Amanda Y Chong

引用次数: 0

Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6. 我们所有人研究计划v6中来自TCGA的罕见致病变异的交集。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-01-11 DOI: 10.1016/j.xhgg.2025.100405

Blaine A Bates, Kylee E Bates, Spencer A Boris, Colin Wessman, David Stone, Justin Bryan, Mary F Davis, Matthew H Bailey

{"title":"Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6.","authors":"Blaine A Bates, Kylee E Bates, Spencer A Boris, Colin Wessman, David Stone, Justin Bryan, Mary F Davis, Matthew H Bailey","doi":"10.1016/j.xhgg.2025.100405","DOIUrl":"10.1016/j.xhgg.2025.100405","url":null,"abstract":"Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.8 × 10-7), AFR (p = 0.018), and MID (p = 0.0083) genetic similarity groups who carry a rare pathogenic mutation are more likely to have cancer than those without a rare pathogenic mutation. With the advent of combining medical records and genetic mutations, we also performed a phenome-wide association study (PheWAS) to assess the effect of pathogenic variants on additional phenotypes. This analysis again showed several associations between predisposition variants and cancer in EUR-like participants, but fewer in those of the other genetic similarity groups. As All of Us grows to 1 million participants, our projections suggest sufficient power (>99%) to detect cancer-associated variants that are common, but limited power (∼28%) to detect rare mutations when using the entire cohort. This study provides preliminary insights into genetic predispositions to cancer across a diverse cohort and demonstrates the value of All of Us as a resource for cancer research.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100405"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971088","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}

引用次数: 0

Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency. 蛋白酶体激活可改善与fbxo11缺乏相关的神经元表型。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-03-20 DOI: 10.1016/j.xhgg.2025.100425

Anne Gregor, Laila Distel, Arif B Ekici, Philipp Kirchner, Steffen Uebe, Mandy Krumbiegel, Soeren Turan, Beate Winner, Christiane Zweier

{"title":"Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency.","authors":"Anne Gregor, Laila Distel, Arif B Ekici, Philipp Kirchner, Steffen Uebe, Mandy Krumbiegel, Soeren Turan, Beate Winner, Christiane Zweier","doi":"10.1016/j.xhgg.2025.100425","DOIUrl":"10.1016/j.xhgg.2025.100425","url":null,"abstract":"Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous system-related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR-Cas9 and a Drosophila model using tissue-specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration, and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome-activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100425"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671209","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}

引用次数: 0

An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome. 一项开放标签研究评估AMO-01治疗费伦-麦克德米综合征癫痫发作的安全性和有效性。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2024-12-16 DOI: 10.1016/j.xhgg.2024.100393

Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison McMorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon

{"title":"An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome.","authors":"Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison McMorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon","doi":"10.1016/j.xhgg.2024.100393","DOIUrl":"10.1016/j.xhgg.2024.100393","url":null,"abstract":"Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion of AMO-01 at 120 mg/m2 was administered to six participants using an open-label design. Safety was assessed during the infusion and for 4 weeks post-infusion. Caregivers completed seizure diaries and recorded individual seizures during a baseline period and for 4 weeks following the infusion. Exploratory clinical and biomarker assessments were completed throughout the study. AMO-01 was well tolerated, with no serious adverse events (AEs) reported. All AEs were mild or moderate in severity. Seizures were reduced by at least 25% compared to baseline at each follow-up (weeks 1, 2, and 4). Exploratory clinical measures did not change significantly from baseline, but visual evoked potentials (VEPs) and phosphorylated ERK blood levels revealed trending changes in a subset of participants. These results provide preliminary support for the safety of AMO-01 and its efficacy in reducing seizures in adults with PMS. Future placebo-controlled studies with larger sample sizes and repeated dosing are warranted.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100393"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847746","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}

引用次数: 0

Families' experiences of receiving adult- and pediatric-onset genetic results. 家庭接受成人和儿科发病基因结果的经验。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-02-12 DOI: 10.1016/j.xhgg.2025.100416

Jessica Goehringer, Tracey Leitzel, Muki Kunnmann, Alyson E Floyd, Sean O'Dell, Jessica Mozersky, Alanna Kulchak Rahm, Adam H Buchanan

{"title":"Families' experiences of receiving adult- and pediatric-onset genetic results.","authors":"Jessica Goehringer, Tracey Leitzel, Muki Kunnmann, Alyson E Floyd, Sean O'Dell, Jessica Mozersky, Alanna Kulchak Rahm, Adam H Buchanan","doi":"10.1016/j.xhgg.2025.100416","DOIUrl":"10.1016/j.xhgg.2025.100416","url":null,"abstract":"There is a scarcity of empirical data on the potential psychosocial and behavioral effects of returning genomic results for adult-onset conditions not medically actionable in pediatric patients. Potential harms include distress, discrimination, loss of future autonomy, or family functioning changes. The Pediatric Reporting of Genomic Results Study (PRoGRESS) explores outcomes of disclosing pediatric- and adult-onset genomic findings to families in an observational trial. Participants include adolescents (ages 11-17) with a genetic variant identified and returned through Geisinger's MyCode Genomic Screening and Counseling Program and their parents. This program involves returning pathogenic and likely pathogenic variants in a list of genes consistent with the American College of Medical Genetics and Genomics secondary findings list. Parents and adolescents with pediatric- and adult-onset results were invited to participate in interviews at 1 and 12 months post results disclosure. Here, we report the results of a qualitative analysis that included data from 25 participants with a known family history of a variant. Families generally had positive or neutral experiences with learning and adjusting to the results, and, on balance, felt it was beneficial to have the result. Previously proposed hypothetical concerns regarding disclosing adult-onset results to children were not reported in this cohort. Our findings provide guidance on supporting families in preparing for and adjusting to genomic results related to adult-onset conditions, particularly in care-delivery systems that are not designed to support families as the information becomes clinically relevant and provide evidence that longitudinal support may benefit families with an adult- or pediatric-onset result.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100416"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411083","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}

引用次数: 0

Evaluation of imputation performance of multiple reference panels in a Pakistani population. 巴基斯坦人群中多个参考小组的归责表现评价。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2024-12-18 DOI: 10.1016/j.xhgg.2024.100395

Jiayi Xu, Dongjing Liu, Arsalan Hassan, Giulio Genovese, Alanna C Cote, Brian Fennessy, Esther Cheng, Alexander W Charney, James A Knowles, Muhammad Ayub, Roseann E Peterson, Tim B Bigdeli, Laura M Huckins

引用次数: 0

Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay. 在患有多种先天性异常和发育迟缓的个体中发现ARHGEF40中p.a g225残基的错义变异。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2025-01-20 DOI: 10.1016/j.xhgg.2025.100408

Melanie P Napier, Erin Ryan, Adi Reich, Joshua A Suhl, Diane Masser-Frye, Marilyn Jones, Celese Beaudreau, Nathaniel Robin, Dana Goodloe, Leandra Folk, Michelle M Morrow, Deanna Alexis Carere

引用次数: 0

Mapping dynamic regulation of gene expression using single-cell transcriptomics and application to complex disease genetics. 利用单细胞转录组学绘制谱系特异性基因表达动态调控的景观，并应用于复杂疾病的遗传学。

IF 3.3

HGG Advances Pub Date : 2025-04-10 Epub Date: 2024-12-31 DOI: 10.1016/j.xhgg.2024.100397

Hanna Abe, Phillip Lin, Dan Zhou, Douglas M Ruderfer, Eric R Gamazon

{"title":"Mapping dynamic regulation of gene expression using single-cell transcriptomics and application to complex disease genetics.","authors":"Hanna Abe, Phillip Lin, Dan Zhou, Douglas M Ruderfer, Eric R Gamazon","doi":"10.1016/j.xhgg.2024.100397","DOIUrl":"10.1016/j.xhgg.2024.100397","url":null,"abstract":"Single-cell transcriptome data can provide insights into how genetic variation influences biological processes involved in human physiology and disease. However, the identification of gene-level associations in distinct cell types faces several challenges, including the limited reference resources from population-scale studies, data sparsity in single-cell RNA sequencing, and the complex cell state pattern of expression within individual cell types. Here, we develop genetic models of cell-type-specific and cell-state-adjusted gene expression in mid-brain neurons undergoing differentiation from induced pluripotent stem cells. The resulting framework quantifies the dynamics of the genetic regulation of gene expression and estimates its cell-type specificity. As an application, we show that the approach detects known and new genes associated with schizophrenia and enables insights into context-dependent disease mechanisms. We provide a genomic resource from a phenome-wide application of our models to more than 1,500 phenotypes from the UK Biobank. Using longitudinal, genetically determined expression, we implement a predictive causality framework, evaluating the prediction of future values of a target gene expression using prior values of a putative regulatory gene. Collectively, the results of this work demonstrate the insights that can be gained into the molecular underpinnings of disease by quantifying the genetic control of gene expression at single-cell resolution.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100397"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915801","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}

引用次数: 0