Journal of Human Genetics最新文献_第4页

The genetic architecture of age at menarche and its causal effects on other traits 月经初潮年龄的遗传结构及其对其他特征的因果效应。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-15 DOI: 10.1038/s10038-024-01287-w

Gui-Juan Feng, Qian Xu, Qi-Gang Zhao, Bai-Xue Han, Shan-Shan Yan, Jie Zhu, Yu-Fang Pei

{"title":"The genetic architecture of age at menarche and its causal effects on other traits","authors":"Gui-Juan Feng, Qian Xu, Qi-Gang Zhao, Bai-Xue Han, Shan-Shan Yan, Jie Zhu, Yu-Fang Pei","doi":"10.1038/s10038-024-01287-w","DOIUrl":"10.1038/s10038-024-01287-w","url":null,"abstract":"Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10−8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 12","pages":"645-653"},"PeriodicalIF":2.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988157","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

Japanese Public Health Insurance System’s new genomic strategic action to shorten the “diagnostic odyssey” for patients with rare and intractable diseases 日本公共健康保险制度的新基因组战略行动，以缩短罕见病和疑难杂症患者的 "诊断奥德赛"。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-15 DOI: 10.1038/s10038-024-01285-y

Jiro Ezaki, Yukari Takahashi, Harutaka Saijo, Fuyuki Miya, Kenjiro Kosaki

{"title":"Japanese Public Health Insurance System’s new genomic strategic action to shorten the “diagnostic odyssey” for patients with rare and intractable diseases","authors":"Jiro Ezaki, Yukari Takahashi, Harutaka Saijo, Fuyuki Miya, Kenjiro Kosaki","doi":"10.1038/s10038-024-01285-y","DOIUrl":"10.1038/s10038-024-01285-y","url":null,"abstract":"In June 2024, the Japanese government introduced a new genomic strategic action to shorten the “diagnostic odyssey” for patients with rare and intractable diseases: Six groups of rare diseases, (i) Muscle weakness group, (ii) Growth retardation, intellectual disability, and characteristic facial features group, (iii) Intellectual disability/epilepsy group, (iv) Cardiomyopathy group (mainly adult onset) (v) Proteinuria group, (vi) Fever, inflammation, skin rash, osteoarthritis group, have been newly recognized as “difficult-to-differentiate disorders” and comprehensive genomic testing can be reimbursed when patients belong to one of the six groups and certain requirements are met. The introduction of comprehensive genomic testing will improve the diagnosis rate of diseases and have significant potential to enhance Japan’s rare and intractable disease policy. The new strategy in Japan and its rationale will be a reference for insurance reimbursement of comprehensive genomic testing in other countries that have universal health coverage supported by the public health insurance system.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 11","pages":"549-552"},"PeriodicalIF":2.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988156","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

Reciprocal chromosome translocation t(3;4)(q27;q31.2) with deletion of 3q27 and reduced FBXW7 expression in a patient with developmental delay, hypotonia, and seizures 一名发育迟缓、肌张力低下和癫痫发作患者的染色体互变t(3;4)(q27;q31.2)，伴有3q27缺失和FBXW7表达减少。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-09 DOI: 10.1038/s10038-024-01286-x

Takeaki Tamura, Keiko Shimojima Yamamoto, Jun Tohyama, Ichiro Morioka, Hitoshi Kanno, Toshiyuki Yamamoto

{"title":"Reciprocal chromosome translocation t(3;4)(q27;q31.2) with deletion of 3q27 and reduced FBXW7 expression in a patient with developmental delay, hypotonia, and seizures","authors":"Takeaki Tamura, Keiko Shimojima Yamamoto, Jun Tohyama, Ichiro Morioka, Hitoshi Kanno, Toshiyuki Yamamoto","doi":"10.1038/s10038-024-01286-x","DOIUrl":"10.1038/s10038-024-01286-x","url":null,"abstract":"Reciprocal chromosomal translocation is one of genomic variations. When cytogenetically de novo reciprocal translocations are identified in patients with some clinical manifestations, the genes in the breakpoints are considered to be related to the clinical features. In this study, we encountered a patient with severe developmental delay, intractable epilepsy, growth failure, distinctive features, and skeletal manifestations. Conventional karyotyping revealed a de novo translocation described as 46,XY,t(3;4)(q27;q31.2). Chromosomal microarray testing detected a 1.25-Mb microdeletion at 3q27.3q28. Although the skeletal manifestations may have been affected by this deletion, the neurological features of this patient were severe and could not be fully explained by this deletion. Since no genomic copy number aberration was detected on chromosome 4, long-read whole-genome sequencing analysis was performed and a precise breakpoint was confirmed. A 460-bp deletion was detected between the two breakpoints; however, no gene was disrupted. FBXW7, the gene responsible for developmental delay, hypotonia, and impaired language, is in the 0.5-Mb telomeric region. Most of the patient’s clinical features were considered consistent with symptoms of FBXW7-related disorders, but were more severe. FBXW7 expression in the immortalized lymphoblasts of the patient was reduced compared to that in controls. Based on these findings, we suspect that FBXW7 is affected by downstream position effects of chromosomal translocations. The severe neurological features of the patient may have been affected not only by the 3q27-q28 deletion but also by impaired expression of FBXW7 derived from the breakage of chromosome 4.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 12","pages":"639-644"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912929","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

Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield 探索无脑畸形谱系的未决病例：整合外显子组和基因组测序以提高诊断率。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-09 DOI: 10.1038/s10038-024-01283-0

Shogo Furukawa, Mitsuhiro Kato, Akihiko Ishiyama, Tomohiro Kumada, Takeshi Yoshida, Eri Takeshita, Pin Fee Chong, Hideo Yamanouchi, Yuko Kotake, Takayoshi Kyoda, Toshihiro Nomura, Yohane Miyata, Mitsuko Nakashima, Hirotomo Saitsu

{"title":"Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield","authors":"Shogo Furukawa, Mitsuhiro Kato, Akihiko Ishiyama, Tomohiro Kumada, Takeshi Yoshida, Eri Takeshita, Pin Fee Chong, Hideo Yamanouchi, Yuko Kotake, Takayoshi Kyoda, Toshihiro Nomura, Yohane Miyata, Mitsuko Nakashima, Hirotomo Saitsu","doi":"10.1038/s10038-024-01283-0","DOIUrl":"10.1038/s10038-024-01283-0","url":null,"abstract":"Lissencephaly is a rare brain malformation characterized by abnormal neuronal migration during cortical development. In this study, we performed a comprehensive genetic analysis using next-generation sequencing in 12 unsolved Japanese lissencephaly patients, in whom PAFAH1B1, DCX, TUBA1A, and ARX variants were excluded using the Sanger method. Exome sequencing (ES) was conducted on these 12 patients, identifying pathogenic variants in CEP85L, DYNC1H1, LAMC3, and DCX in four patients. Next, we performed genome sequencing (GS) on eight unsolved patients, and structural variants in PAFAH1B1, including an inversion and microdeletions involving several exons, were detected in three patients. Notably, these microdeletions in PAFAH1B1 could not to be detected by copy number variation (CNV) detection tools based on the depth of coverage methods using ES data. The density of repeat sequences, including Alu sequences or segmental duplications, which increase the susceptibility to structural variations, is very high in some lissencephaly spectrum genes (PAFAH1B1, TUBA1A, DYNC1H1). These missing CNVs were due to the limitations of detecting repeat sequences in ES-based CNV detection tools. Our study suggests that a combined approach integrating ES with GS can contribute to a higher diagnostic yield and a better understanding of the genetic landscape of the lissencephaly spectrum.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 12","pages":"629-637"},"PeriodicalIF":2.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912928","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

Efficient HLA imputation from sequential SNPs data by transformer 通过转换器从序列 SNPs 数据中高效推算 HLA。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-02 DOI: 10.1038/s10038-024-01278-x

Kaho Tanaka, Kosuke Kato, Naoki Nonaka, Jun Seita

{"title":"Efficient HLA imputation from sequential SNPs data by transformer","authors":"Kaho Tanaka, Kosuke Kato, Naoki Nonaka, Jun Seita","doi":"10.1038/s10038-024-01278-x","DOIUrl":"10.1038/s10038-024-01278-x","url":null,"abstract":"Human leukocyte antigen (HLA) genes are associated with a variety of diseases, yet the direct typing of HLA alleles is both time-consuming and costly. Consequently, various imputation methods leveraging sequential single nucleotide polymorphisms (SNPs) data have been proposed, employing either statistical or deep learning models, such as the convolutional neural network (CNN)-based model, DEEP*HLA. However, these methods exhibit limited imputation efficiency for infrequent alleles and necessitate a large size of reference dataset. In this context, we have developed a Transformer-based model to HLA allele imputation, named “HLA Reliable IMpuatioN by Transformer (HLARIMNT)” designed to exploit the sequential nature of SNPs data. We evaluated HLARIMNT’s performance using two distinct reference panels; Pan-Asian reference panel (n = 530) and Type 1 Diabetes genetics Consortium (T1DGC) reference panel (n = 5225), alongside a combined panel (n = 1060). HLARIMNT demonstrated superior accuracy to DEEP*HLA across several indices, particularly for infrequent alleles. Furthermore, we explored the impact of varying training data sizes on imputation accuracy, finding that HLARIMNT consistently outperformed across all data size. These findings suggest that Transformer-based models can efficiently impute not only HLA types but potentially other gene types from sequential SNPs data.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"533-540"},"PeriodicalIF":2.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01278-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878853","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

Genome analysis through image processing with deep learning models 利用深度学习模型通过图像处理进行基因组分析。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01275-0

Yao-zhong Zhang, Seiya Imoto

引用次数: 0

An application supporting diagnosis for rare genetic diseases – UR-DBMS and Syndrome Finder – 支持罕见遗传病诊断的应用程序--UR-DBMS 和 Syndrome Finder。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01277-y

Kenji Naritomi

引用次数: 0

A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia 交替剪接的 VLDLR 第 4 外显子中的一个同卵无义变体会导致一种神经发育障碍，但没有 VLDLR 小脑发育不全的特征。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01279-w

Tess Holling, Ibrahim M. Abdelrazek, Ghada M. Elhady, Marwa Abd Elmaksoud, Seung Woo Ryu, Ebtesam Abdalla, Kerstin Kutsche

{"title":"A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia","authors":"Tess Holling, Ibrahim M. Abdelrazek, Ghada M. Elhady, Marwa Abd Elmaksoud, Seung Woo Ryu, Ebtesam Abdalla, Kerstin Kutsche","doi":"10.1038/s10038-024-01279-w","DOIUrl":"10.1038/s10038-024-01279-w","url":null,"abstract":"VLDLR cerebellar hypoplasia is characterized by intellectual disability, non-progressive cerebellar ataxia, and seizures. The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem. Biallelic VLDLR pathogenic variants cause loss-of-function of the encoded very low-density lipoprotein receptor. VLDLR exons 4 and 16 are alternatively spliced, resulting in the expression of four transcript variants, including two exon 4-lacking mRNAs expressed in the human brain. Previously reported VLDLR pathogenic variants affect all four transcript variants. Here we report on two sisters with facial dysmorphism, microcephaly, intellectual disability, and normal brain imaging. Exome sequencing in one patient identified the homozygous VLDLR nonsense variant c.376C>T; p.(Gln126*) in exon 4; her similarly affected sister also carried the homozygous variant and parents were heterozygous carriers. VLDLR transcript analysis identified mRNAs with and without exon 4 in patient fibroblasts, while exon 4-containing VLDLR mRNAs were predominantly detected in control fibroblasts. We found significantly reduced VLDLR mRNA levels in patient compared to control cells, likely caused by nonsense-mediated mRNA decay of exon 4-containing VLDLR transcripts. Expression of neuronal VLDLR isoforms produced from exon 4-lacking transcripts may have protected both patients from developing the cerebellar hypoplasia phenotype.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 12","pages":"623-628"},"PeriodicalIF":2.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01279-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859949","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

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-19 DOI: 10.1038/s10038-024-01276-z

Lihua Jiang, Yilong Wang, Weiqin Zhang, Xin Zhang, Feng Gao, Zhefeng Yuan

引用次数: 0

Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome- 基于综合序列分析的 GBA1 变异与 MSA 的关联研究--取决于人类参考基因组的短读序列分析的陷阱。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-18 DOI: 10.1038/s10038-024-01266-1

Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Junko Nomoto, Hiroyuki Ishiura, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, NCBN Controls WGS Consortium, Tatsushi Toda, Shoji Tsuji

{"title":"Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome-","authors":"Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Junko Nomoto, Hiroyuki Ishiura, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, NCBN Controls WGS Consortium, Tatsushi Toda, Shoji Tsuji","doi":"10.1038/s10038-024-01266-1","DOIUrl":"10.1038/s10038-024-01266-1","url":null,"abstract":"Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP. To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P–p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38. The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW). Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.85 (95% CI; 1.05 – 7.76, p = 0.0400).","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 12","pages":"613-621"},"PeriodicalIF":2.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01266-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633747","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