Human molecular genetics最新文献

{"title":"Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.","authors":"Neblina Sikta, Samuel Gooley, Timothy E Green, Olivia Hoeper, Tom Witkowski, Caitlin Bennett, David Francis, Joshua Reid, Kevin Mao, Mohammed Awad, Samuel Roberts-Thomson, Kristian Bulluss, Jonathan Clark, Ingrid E Scheffer, Piero Perucca, Mark F Bennett, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand","doi":"10.1093/hmg/ddaf077","DOIUrl":"10.1093/hmg/ddaf077","url":null,"abstract":"<p><p>Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1/CCM1 were found in 3/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4/7 individuals. These 4 individuals were from separate families with germline KRIT1/CCM1 variants. In 8/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1286-1293"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The p.W651fsX666 mutation on COL10A1 results in impaired trimerization of normal collagen X to induce Schmid type Metaphyseal chondrodysplasia.","authors":"Jingye Yang, Jing Zhang, Qingxiang Lu, Haiying Tian, Ke Wang, Zhi Liu, Yu Xiong, Yadong Li, Ning Ma, Hongxia Tian, Zhongxue Zhou, Ding'an Zhou","doi":"10.1093/hmg/ddaf071","DOIUrl":"10.1093/hmg/ddaf071","url":null,"abstract":"<p><p>Haploinsufficiency resulting from the degradation of mutant Collagen Type X Alpha 1 Chain (COL10A1) mRNA by nonsense-mediated decay (NMD) has been attributed to the pathogenesis of Schmid-type metaphyseal chondrodysplasia (SMCD) in cases involving nonsense mutations. However, this mechanism does not fully explain the complexity of SMCD. In this study, we identified a c.1951_1952 InsT (p.W651 fsX666) mutation in exon 3 of COL10A1 that is associated with chondrodysplasia phenotypes in a two-generation family with SMCD. The mRNA decay of the mutant COL10A1 (named as affected E666X-COL10A1) is caused by the p.W651fsX666 mutation, which also disrupts the trimerization of normal collagen X. However, the mutant mRNA decay of affected exogenous E666X-COL10A1, as well as the complete degradation of E666X-COL10A1 mRNA in the proband, is not significantly induced by the W651fsX666 mutation. In vitro trimerization analyses results indicate that the trimerization of normal collagen X and wild-type collagen X are disrupted by W651fsX666 and E666X-collagen X mutations, respectively, suggesting that the mutant allele collagen X may impose a dominant-negative effect on the normal collagen X. Our results are the first to reveal that the impaired trimerization of normal collagen X is caused by the W651fsX666 mutation and a dominant-negative effect on the normal allele collagen X exerted by the mutant allele collagen X, causing impaired trimerization of collagen X, which will interpret the phenotype variability among the affected individuals in the pedigree with metaphyseal chondrodysplasia type Schmid (MCDS) studied.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1265-1285"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E.","authors":"Dennis O Pérez-López, Audrey A Shively, F Javier Llorente Torres, Roxanne Muchow, Zaid Abu-Salah, Mohammed T Abu-Salah, Jackson T Veltrop, Michael L Garcia, Catherine L Smith, D D W Cornelison, Nicole L Nichols, Monique A Lorson, Christian Lorson","doi":"10.1093/hmg/ddaf080","DOIUrl":"10.1093/hmg/ddaf080","url":null,"abstract":"<p><p>Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated two orthologous NEFLE396K mutation in the mouse C57BL/6 J background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing. Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1313-1327"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H3Africa: a model for implementing biobank-based genomic research in resource-constrained settings.","authors":"Dhriti Sengupta, Ananyo Choudhury, Michèle Ramsay","doi":"10.1093/hmg/ddaf113","DOIUrl":"https://doi.org/10.1093/hmg/ddaf113","url":null,"abstract":"<p><p>The Human Heredity and Health in Africa (H3Africa) consortium was initiated in 2012 to develop an enabling environment for fundamental and applied genomic research in Africa. By 2024, H3Africa included over 500 researchers across 30 African countries and had contributed to supporting 480 PhD graduates and 467 trainees, held over 200 workshops, and published over 700 papers. A distinguishing feature of this consortium was that the model enabled research to be led by African scientists and targeted research questions relevant to African populations. Prompted by the limited infrastructure, resources, and skills to conduct such research projects in most African countries, the consortium dedicated its early efforts and funding toward developing infrastructure and resources such as DNA biorepositories, bioinformatics capacity and ethical and legal guidelines to support such projects. The consortium operated under a complex framework that included a coordinating center, research projects, collaborative centers, and supporting infrastructure such as the biorepositories and the Pan-African bioinformatics network (H3ABioNet). In this brief review, we summarized some of the major contributions of H3Africa to omics research and towards developing a sustainable research enterprise in Africa. Although the funding for the consortium formally ended in 2023, H3Africa continues to sustain its core resources and generate new datasets, publications and collaborations. Given the limited genomic representation of the global south in complex trait genetics research, we illustrate the ways in which the H3Africa consortium is a template for transnational omics research in a resource-constrained setting.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Concern: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.","authors":"","doi":"10.1093/hmg/ddaf099","DOIUrl":"10.1093/hmg/ddaf099","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1254"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease.","authors":"Vera Serebryany-Piavsky, Lian Egulsky, Julia Elia Manoim-Wolkovitz, Saar Anis, Sharon Hassin-Baer, Moshe Parnas, Mia Horowitz","doi":"10.1093/hmg/ddaf062","DOIUrl":"10.1093/hmg/ddaf062","url":null,"abstract":"<p><p>Parkinson disease (PD) is the second most common neurodegenerative disease. While most cases are sporadic, in ~ 5%-10% of PD patients the disease is caused by mutations in several genes, among them GBA1 (glucocerebrosidase beta 1) and LRRK2 (leucine-rich repeat kinase 2), both prevalent among the Ashkenazi Jewish population. LRRK2-associated PD tends to be milder than GBA1-associated PD. Several recent clinical studies have suggested that carriers of both GBA1 and LRRK2 mutations develop milder PD compared to that observed among GBA1 carriers. These findings strongly suggested an interplay between the two genes in the development and progression of PD. In the present study Drosophila was employed as a model to investigate the impact of mutations in the LRRK2 gene on mutant GBA1-associated PD. Our results strongly indicated that flies expressing both mutant genes exhibited milder parkinsonian signs compared to the disease developed in flies expressing only a GBA1 mutation. This was corroborated by a decrease in the ER stress response, increase in the number of dopaminergic cells, elevated levels of tyrosine hydroxylase, reduced neuroinflammation, improved locomotion and extended survival. Furthermore, a significant decrease in the steady-state levels of mutant GBA1-encoded GCase was observed in the presence of mutant LRRK2, strongly implying a role for mutant LRRK2 in degradation of mutant GCase.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1184-1203"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Concern: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.","authors":"","doi":"10.1093/hmg/ddaf097","DOIUrl":"10.1093/hmg/ddaf097","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1252"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction is driven by imbalanced fission and fusion of mitochondria in myofibrillar myopathy type 5.","authors":"Wenjing Wu, Xiaoqing Lv, Yifei Feng, Mengqi Yang, Guiguan Yang, Dandan Zhao, Chuanzhu Yan, Pengfei Lin","doi":"10.1093/hmg/ddaf051","DOIUrl":"10.1093/hmg/ddaf051","url":null,"abstract":"<p><p>Myofibrillar myopathy type 5 (MFM5) is a dominantly inherited myopathy caused by mutations in the FLNC gene. The underlying pathogenic mechanisms of MFM5 remain unclear, and there are currently no effective treatments available. This study hypothesizes that mitochondrial dysfunction plays a key role in the pathogenesis of MFM5, on the basis of the COX-negative fibres observed in MFM5 patients. To test this hypothesis, a zebrafish model was developed to explore the impact of filamin-C on mitochondrial dynamics. These results demonstrated that defects in filamin-C disrupt mitochondrial fission, leading to mitochondrial dysfunction and mitophagy. This hypothesis was further validated through the analysis of skeletal muscle samples from MFM5 patients. These findings suggest that mitochondrial dysfunction caused by imbalanced fission and fusion of mitochondria and mitophagy contributes to MFM5 pathology. Importantly, this study identified potential therapeutic targets for MFM5 treatment, opening avenues for future research aimed at developing targeted interventions.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1173-1183"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci.","authors":"Jinyoung Byun, Younghun Han, Jiyeon Choi, Ryan Sun, Vikram R Shaw, Catherine Zhu, Xiangjun Xiao, Christine Lusk, Hoda Badr, Hyun-Sung Lee, Hee-Jin Jang, Yafang Li, Hyeyeun Lim, Erping Long, Yanhong Liu, Linda Kachuri, Kyle M Walsh, John K Wiencke, Demetrius Albanes, Stephen Lam, Adonina Tardon, Marian L Neuhouser, Matt J Barnett, Chu Chen, Stig Bojesen, Hermann Brenner, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeböller, David C Christiani, Gad Rennert, Susanne Arnold, John K Field, Sanjay Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Fiona Taylor, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Alpa Patel, Xihong Lin, Krista A Zanetti, Curtis C Harris, Stephen Chanock, James McKay, Ann G Schwartz, Rayjean J Hung, Christopher I Amos","doi":"10.1093/hmg/ddaf059","DOIUrl":"10.1093/hmg/ddaf059","url":null,"abstract":"<p><p>Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer focused on studying African Americans, comprising 2267 lung cancer cases and 4264 controls. We identified three loci associated with lung cancer, one with lung adenocarcinoma, and four with lung squamous cell carcinoma in this population at the genomic-wide significance level. Among them, three novel loci were identified near VWF at 12p13.31 for overall lung cancer and GACAT3 at 2p24.3 and LMAN1L at 15q24.1 for lung squamous cell carcinoma. In addition, we confirmed previously reported risk loci with known or new lead variants near CHRNA5 at 15q25.1 and CYP2A6 at 19q13.2 associated with lung cancer and TRIP13 at 5p15.33 and ERC1 at 12p13.33 associated with lung squamous cell carcinoma. Further multi-step functional analyses shed light on biological mechanisms underlying these associations of lung cancer in this population. Our study highlights the importance of ancestry-specific studies for the potential alleviation of lung cancer burden in African Americans.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1227-1237"},"PeriodicalIF":3.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare DCM associated variants in pre-miR-208a disrupt miRNA maturation and function.","authors":"Yolan J Reckman, Jan Haas, Ingeborg van der Made, Simon G Williams, Iria Gomez Diaz, Mohammed Akhtar, Jens Mogensen, Torsten B Rasmussen, Eric Villard, Philippe Charron, Perry Elliott, Bernard D Keavney, Lorenzo Monserrat, Yigal M Pinto, Benjamin Meder, Anke J Tijsen","doi":"10.1093/hmg/ddaf069","DOIUrl":"10.1093/hmg/ddaf069","url":null,"abstract":"<p><p>Dilated cardiomyopathy (DCM) is a major cause of heart failure (HF) defined by ventricular dilatation and systolic dysfunction. Although microRNAs (miRNAs) are known to affect HF development, little is known about the contribution of genetic variants in miRNAs or their precursors to the susceptibility or pathogenesis of DCM. We screened 1640 DCM cases for variants in cardiac miR-208a and miR-208b and their precursors. We identified four variants in the miR-208a pre-miRNA, which are present at very low frequencies in the general population. Two of these variants (+42G > T and +68G > T) alter a highly conserved nucleotide and the predicted pre-miRNA secondary structure. Both variants result in reduced mature miR-208a levels in overexpression experiments. The variant +42G > T also increased pre-miR-208a levels in these experiments, which indicates a maturation deficiency. Co-transfection of the overexpression constructs with a luciferase construct containing six miRNA binding sites revealed that both variants also impair repression of luciferase expression by miR-208a, indicative of also a loss of miR208a function. Together this indicates that these DCM-associated variants impair formation of mature miR208a. Combined with the role of miR-208a in cardiac contractility this suggests that variants +42G > T and +68G > T in pre-miR-208a may contribute to the DCM phenotype observed in these patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1216-1226"},"PeriodicalIF":3.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}