Journal of Human Genetics最新文献_第5页

Genome-wide analysis of 3′ untranslated region alternative polyadenylation quantitative trait loci identified a potential novel susceptibility locus for lung cancer in cross-ancestry populations 对3'非翻译区选择性多聚腺苷酸化数量性状位点的全基因组分析发现了一个潜在的新的跨祖先人群肺癌易感位点。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-29 DOI: 10.1038/s10038-025-01375-5

Yi Wang, Yuancheng Li, Ting Tian, Renfang Han, Nimei Zeng, Fangfei Xie, Yun Wang, Jingyi Fan

{"title":"Genome-wide analysis of 3′ untranslated region alternative polyadenylation quantitative trait loci identified a potential novel susceptibility locus for lung cancer in cross-ancestry populations","authors":"Yi Wang, Yuancheng Li, Ting Tian, Renfang Han, Nimei Zeng, Fangfei Xie, Yun Wang, Jingyi Fan","doi":"10.1038/s10038-025-01375-5","DOIUrl":"10.1038/s10038-025-01375-5","url":null,"abstract":"Genome wide association studies (GWASs) have revealed several lung cancer susceptibility loci; however, we still face key issues such as how to identify more ‘high-frequency and inefficient’ variants and decipher the causal variants. Alternative polyadenylation (APA) can shorten or prolong the 3′UTR of mRNA containing cis regulatory elements, which plays an important role in post transcriptional regulation. Specific variants can affect the 3′UTR APA, leading to differences in the risk of lung cancer among individuals carrying different alleles. In this study, a cross-ancestry two-stage case-control design was used to evaluate the associations of 3′UTR APA related variants (3′aQTL SNPs, 3′aSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on the genome-wide meta-analysis (GWMA) from FinnGen, UK Biobank and VA Million Veteran Program (MVP), including 28,557 cases and 1,355,961 controls. The promising variants were validated in an independent Chinese population with 1169 lung cancer cases and 1046 controls. Functional annotations of the identified 3′aSNP and related genes were performed based on multiple public databases. Finally, we identified a potential 3′aSNP rs11583258 associated with the risk of lung cancer both in the GWMA [OR = 1.04 (1.02–1.06), P = 1.00 × 10–4] and in the validation stage [OR = 1.08 (1.01–1.16), P = 1.01 × 10–2] at 1p36.11. Function annotation integrating the results of multiple public datasets suggested the variants in this region might affect both the length of the 3′UTR of the UBXN11 transcripts and the expression of UBXN11 to affect the susceptibility of lung cancer.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"529-536"},"PeriodicalIF":2.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NGLY1 deficiency - clinical features and therapeutic strategy. NGLY1缺乏症的临床特征及治疗策略。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-29 DOI: 10.1038/s10038-025-01376-4

Haruhiko Fujihria, Hiroto Hirayama, Tadashi Suzuki

{"title":"NGLY1 deficiency - clinical features and therapeutic strategy.","authors":"Haruhiko Fujihria, Hiroto Hirayama, Tadashi Suzuki","doi":"10.1038/s10038-025-01376-4","DOIUrl":"https://doi.org/10.1038/s10038-025-01376-4","url":null,"abstract":"NGLY1 deficiency is a rare autosomal recessive genetic disorder caused by biallelic mutations of the human NGLY1 gene. NGLY1 encodes the cytosolic peptide:N-glycanase (PNGase; NGLY1 in mammals), which plays essential roles in cytosolic glycan degradation (non-lysosomal glycan degradation), the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins, and the complete activation of the transcription factor nuclear factor erythroid 2-like 1 (NEF2L1). NFE2L1 contributes to the regulation of the expression of proteasome subunits and oxidative stress responses. Patients with NGLY1 deficiency exhibit multisystemic clinical features, including global developmental delay, peripheral neuropathy, hypolacrima or alacrima, and the transient elevation of liver transaminases. To date, more than 100 individuals with NGLY1 deficiency and over 70 distinct pathogenic mutations in the NGLY1 gene have been reported. There is currently no approved therapy for this disorder. Moreover, the underlying pathogenic mechanism, including the correlation between patients' symptoms and mutant alleles, remains poorly understood. In this review, we summarize the most frequently reported NGLY1 mutations and their associated clinical features. We also present an overview of the current therapeutic strategy for NGLY1 deficiency.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Broadening the mutational spectrum of ASAH1, as a susceptibility gene for keloids 拓宽了瘢痕疙瘩易感基因ASAH1的突变谱。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-25 DOI: 10.1038/s10038-025-01367-5

Sepideh Hamzehlou, Chao Xing, Donald A. Glass II

引用次数: 0

Diagnostic yield of trio exome sequencing as a first-tier test for identifying genetic causes of pregnancy loss 三重奏外显子组测序的诊断产量作为鉴定遗传原因流产的一级测试。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-24 DOI: 10.1038/s10038-025-01373-7

Lina Xiang, Anqi Deng, Jie Zhou, Xuefan Dong, Wenbo Mu, Qi Zhang, Jing Zhang, Sha Tang, Ping Fang, Xiaoqiang Cai

{"title":"Diagnostic yield of trio exome sequencing as a first-tier test for identifying genetic causes of pregnancy loss","authors":"Lina Xiang, Anqi Deng, Jie Zhou, Xuefan Dong, Wenbo Mu, Qi Zhang, Jing Zhang, Sha Tang, Ping Fang, Xiaoqiang Cai","doi":"10.1038/s10038-025-01373-7","DOIUrl":"10.1038/s10038-025-01373-7","url":null,"abstract":"Genetic defects are a major cause of pregnancy loss, leading to fetal death or elective abortion due to congenital anomalies. This study evaluates the effectiveness of trio exome sequencing (ES) in identifying genetic causes of pregnancy loss. Trio ES was used as a first-tier genetic test on 193 cases of pregnancy loss to detect both chromosomal abnormalities and small variants potentially linked to fetal death and anomalies. The pathogenicity of identified variants was assessed, and the diagnostic yield was analyzed. Trio ES provided an overall diagnostic yield of 24% (47/193) across this cohort, with a similar positive rate observed in fetal death (26%, 12/45) and elective abortion (23%, 35/148) groups. Among diagnosed cases, 45% (21/47) were attributed to chromosomal abnormalities, while 55% (26/47) were caused by small variants. This suggests that ES more than doubled the positive rates compared to traditional methods such as karyotyping and chromosomal microarray analysis. Notably, chromosomal abnormalities were the primary cause of fetal death (75%, 9/12), whereas small variants were more prevalent in elective abortion cases (68%, 24/35), particularly those with central nervous and skeletal anomalies. Additional candidate variants were identified in 35 inconclusive cases (18%), potentially further increasing the detection rate. This study highlights the value of trio ES in diagnosing genetic causes of pregnancy loss. Implementing it as a first-tier test can significantly enhance our understanding of fetal death and anomalies, therefore facilitating informed future pregnancy management.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"517-527"},"PeriodicalIF":2.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review 扩展tbc1d32相关纤毛病的临床和分子谱：病例报告和文献综述

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-23 DOI: 10.1038/s10038-025-01371-9

Wongsathorn Eiumtrakul, Thipwimol Tim-Aroon, Wadakarn Wuthisiri, Tharikarn Sujirakul, Thanissara Chansakul, Arthaporn Khongkraparn, Saisuda Noojarern, Duangrurdee Wattanasirichaigoon, Parith Wongkittichote

{"title":"Expanding the clinical and molecular spectrum of TBC1D32-related ciliopathy: case reports and literature Review","authors":"Wongsathorn Eiumtrakul, Thipwimol Tim-Aroon, Wadakarn Wuthisiri, Tharikarn Sujirakul, Thanissara Chansakul, Arthaporn Khongkraparn, Saisuda Noojarern, Duangrurdee Wattanasirichaigoon, Parith Wongkittichote","doi":"10.1038/s10038-025-01371-9","DOIUrl":"10.1038/s10038-025-01371-9","url":null,"abstract":"Genetic defects in primary cilia-related genes are associated with a heterogeneous group of disorders known as ciliopathies. TBC1D32-related ciliopathy presents with a broad phenotypic spectrum, ranging from isolated retinal diseases to severe multisystemic involvement, including fetal demise. We report two unrelated patients with retinal disease and hypopituitarism, with one also exhibiting facial dysmorphism, developmental delay, and unilateral oculomotor nerve palsy. Whole genome sequencing identified biallelic TBC1D32 variants in both patients, including two splice-site variants. RNA analysis revealed exon skipping, leading to frameshift and premature protein truncation. A review of previously reported cases highlighted facial dysmorphism, retinal disease, and hypopituitarism as major clinical features of TBC1D32-related ciliopathy. Additionally, we propose oculomotor nerve palsy as an extended clinical feature of this disorder. This study expands the clinical and molecular spectrum of TBC1D32-related ciliopathy.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"509-515"},"PeriodicalIF":2.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction 鉴定线粒体疾病患者的致病RNU4-2变异：拓宽线粒体功能障碍的非编码RNA基因变异谱

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-22 DOI: 10.1038/s10038-025-01356-8

Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Taku Omata, Maki Nodera, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Holger Prokisch, Hiroshi Matsumoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki

{"title":"Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: Broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction","authors":"Kohta Nakamura, Yoshihito Kishita, Atsuko Imai-Okazaki, Taku Omata, Maki Nodera, Yukiko Yatsuka, Ayumu Sugiura, Naoyuki Matsumoto, Holger Prokisch, Hiroshi Matsumoto, Akira Ohtake, Kei Murayama, Yasushi Okazaki","doi":"10.1038/s10038-025-01356-8","DOIUrl":"10.1038/s10038-025-01356-8","url":null,"abstract":"Mitochondrial diseases are characterized by impaired energy production due to mitochondrial dysfunction. Despite advances in sequencing technologies, many cases remain genetically undiagnosed. We report two cases of mitochondrial disease harboring identical de novo variant in the non-coding RNA gene RNU4-2, previously associated with neurodevelopmental disorders. Re-analysis of whole genome sequencing data from 357 patients ascertained as possibly having mitochondrial disease (see Methods: Supplementary Data S1) identified two cases with a pathogenic RNU4-2 variant (GRCh38: chr.12:120291839: T > TA; NR_003137.2: n.64_65insT). Both patients exhibited decreased oxygen consumption rates and clinical features including developmental delay, microcephaly, short stature. This study provides the first evidence linking RNU4-2 variant to mitochondrial disease, expanding the phenotypic spectrum associated with this gene. Our findings highlight the importance of re-analyzing genomic data and considering non-coding RNA gene variants in mitochondrial disease diagnostics, potentially improving the diagnosis of previously unsolved cases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"541-543"},"PeriodicalIF":2.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle. 骨骼肌j结构域蛋白相关伴侣病的分子遗传学研究。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-22 DOI: 10.1038/s10038-025-01372-8

Michio Inoue

{"title":"Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.","authors":"Michio Inoue","doi":"10.1038/s10038-025-01372-8","DOIUrl":"10.1038/s10038-025-01372-8","url":null,"abstract":"The J-domain proteins (JDPs), or HSP40s, are essential molecular co-chaperones that, in concert with HSP70, play a pivotal role in maintaining protein homeostasis, which is particularly critical in skeletal muscle. In recent years, pathogenic variants in several JDP-encoding genes have been identified as a cause of a growing group of inherited muscle diseases, termed JDP-related myopathies. This review provides a comprehensive overview of the current understanding of the molecular genetics, clinical phenotypes, muscle pathology, and pathomechanisms of myopathies caused by mutations in DNAJB6, DNAJB4, and DNAJB2. These disorders present with a wide spectrum of clinical features, including limb-girdle or distal weakness, and, in some cases, severe early-onset respiratory failure with axial rigidity. Pathologically, they are often characterized by rimmed vacuoles and sarcoplasmic protein inclusions. The underlying molecular mechanisms all involve disruption of the JDP-HSP70 chaperone system, but they are driven by distinct molecular events specific to each gene and mutation type. While loss-of-function is a primary mechanism for recessive forms of DNAJB4 and DNAJB2 myopathy, a toxic gain-of-function mediated by a dysregulated interaction with HSP70 is emerging as a central pathomechanism for dominant myopathies caused by DNAJB6 and DNAJB4 variants. A dominant-negative effect is proposed for dominant DNAJB2 neuromyopathy. This evolving mechanistic understanding is crucial as it informs the development of targeted therapeutic strategies, moving beyond supportive care. Potential future therapies include gene replacement for loss-of-function disorders, and for gain-of-function diseases, approaches including small molecule inhibitors of the JDP-HSP70 interaction or allele- and isoform-specific knockdown.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In memory of Professor Ichiro Matsuda 纪念松田一郎教授。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-15 DOI: 10.1038/s10038-025-01369-3

Kimitoshi Nakamura

引用次数: 0

Hidden SVA retrotransposon insertion in BRCA1 revealed by nanopore targeted sequencing causes hereditary breast and ovarian cancer 纳米孔靶向测序揭示BRCA1中隐藏的SVA反转录转座子插入导致遗传性乳腺癌和卵巢癌。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-08 DOI: 10.1038/s10038-025-01365-7

Sachiko Ohori, Mina Waraya, Kaoru Fujisaki, Takafumi Sangai, Naomi Araki, Rika Kawata, Keiko Takahashi, Ohsuke Migita, Satomi Mitsuhashi, Yoshihisa Yamano, Fumio Takada

{"title":"Hidden SVA retrotransposon insertion in BRCA1 revealed by nanopore targeted sequencing causes hereditary breast and ovarian cancer","authors":"Sachiko Ohori, Mina Waraya, Kaoru Fujisaki, Takafumi Sangai, Naomi Araki, Rika Kawata, Keiko Takahashi, Ohsuke Migita, Satomi Mitsuhashi, Yoshihisa Yamano, Fumio Takada","doi":"10.1038/s10038-025-01365-7","DOIUrl":"10.1038/s10038-025-01365-7","url":null,"abstract":"In Japan, germline BRCA1/2 genetic testing is extensively used for the diagnosis of hereditary breast and ovarian cancer syndrome (HBOC). However, inconclusive results sometimes complicate clinical management. In this study, we identified an intronic SINE-VNTR-Alu (SVA) insertion in BRCA1 of a proband and her mother, both of whom had inconclusive conventional BRCA1/2 genetic test results, by targeted long-read sequencing (LRS) through the application of nanopore adaptive sampling and Flongle genome amplicon sequencing. We further confirmed splicing aberrations using cDNA quantitative PCR with TaqMan probes and Flongle cDNA amplicon sequencing. Our findings highlighted that, in addition to conventional BRCA1/2 genetic testing, structural variation analysis using targeted LRS is indispensable for the accurate diagnosis of HBOC in certain cases. Furthermore, Flongle amplicon sequencing was demonstrated to be effective for sequencing regions refractory to conventional PCR and Sanger sequencing, particularly repetitive and GC-rich regions, such as retrotransposons.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"503-508"},"PeriodicalIF":2.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VarMeter: a prediction method for the impact of glycogene variants. 变量计：预测糖基因变异影响的方法。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2025-07-08 DOI: 10.1038/s10038-025-01364-8

Shiho Ohno, Noriyoshi Manabe, Tadashi Kaname, Shoko Nishihara, Yoshiki Yamaguchi

{"title":"VarMeter: a prediction method for the impact of glycogene variants.","authors":"Shiho Ohno, Noriyoshi Manabe, Tadashi Kaname, Shoko Nishihara, Yoshiki Yamaguchi","doi":"10.1038/s10038-025-01364-8","DOIUrl":"https://doi.org/10.1038/s10038-025-01364-8","url":null,"abstract":"The clinical relevance of glycans, which play a wide array of physiological roles, is underscored by the emergence of congenital disorders of glycosylation, a group of rare inherited diseases caused by defects in glycan-related genes (glycogenes). Biochemical studies of recombinant proteins and phenotypic analyses in knockout mice are revealing critical insights into the roles of various glycosyltransferases, glycosidases, and glycan-binding proteins. However, the biological functions of numerous glycogenes and their role in disease remain incompletely understood, partly due to human-specific functions that are not recapitulated in model organisms, and partly due to the structural diversity and complexity of glycan modifications, which are difficult to fully assess by conventional methods. A promising complementary strategy is the systematic assessment of human genetic variants, particularly missense mutations, to infer functional consequences. Recent developments in protein structure prediction, exemplified by AlphaFold, are facilitating the development of structure-based approaches to variant interpretation. In this review, we discuss current methodologies for predicting the impact of missense variants using structural information, and introduce VarMeter, a computational framework incorporating 3D structural parameters that has been successfully applied to the prediction of pathogenic variants in the ClinVar database. We also describe VarMeter2, an updated version that integrates AlphaFold-derived pLDDT confidence scores and Mahalanobis distance analysis to improve prediction accuracy, demonstrating its ability to predict pathogenic variants of four glycan-related proteins. These tools offer a novel avenue for uncovering previously unrecognized functions of glycogenes and their links to disease, and contribute to the clinical interpretation of genetic variation.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0