Journal of Human Genetics最新文献_第6页

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

Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts 利用 LAMPLINK 和日本队列鉴定类风湿关节炎的表观 SNP 组合。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-16 DOI: 10.1038/s10038-024-01269-y

Mio Shibata, Aika Terada, Takahisa Kawaguchi, Yoichiro Kamatani, Daigo Okada, Kazuhisa Nagashima, Koichiro Ohmura, Fumihiko Matsuda, Shuji Kawaguchi, Jun Sese, Ryo Yamada

{"title":"Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts","authors":"Mio Shibata, Aika Terada, Takahisa Kawaguchi, Yoichiro Kamatani, Daigo Okada, Kazuhisa Nagashima, Koichiro Ohmura, Fumihiko Matsuda, Shuji Kawaguchi, Jun Sese, Ryo Yamada","doi":"10.1038/s10038-024-01269-y","DOIUrl":"10.1038/s10038-024-01269-y","url":null,"abstract":"Genome-wide association studies have enabled the identification of important genetic factors in many trait studies. However, only a fraction of the heritability can be explained by known genetic factors, even in the most common diseases. Genetic loci combinations, or epistatic contributions expressed by combinations of single nucleotide polymorphisms (SNPs), have been argued to be one of the critical factors explaining some of the missing heritability, especially in oligogenic/polygenic diseases. Rheumatoid arthritis (RA) is a complex disease with more than 100 reported SNP associations, as well as various HLA haplotypes and amino acids; however, many associations between RA and inter-chromosomal SNP combinations are unknown. To discover novel associations of epistatic interactions with high odds ratios in RA, we applied the LAMPLINK method, a systematic enumerative procedure for identifying high-order SNP combinations, to a Japanese RA cohort (discovery cohort; 4024 patients with RA and 7731 controls). We validated the identified associations in a different Japanese cohort (validation cohort; 810 RA patients and 6303 controls). In this study, we identified 90 significant genetic associations in the discovery cohort. Among these, 74 (82.2%) associations were replicated in the validation cohort, and eight combinations were inter-chromosomal, all of which comprised rs7765379 or rs35265698 located in the HLA region. These two SNPs exhibited strong correlations with valine at amino acid position 11 in HLA-DRB1 (HLA-DRB1-11-Val). Finally, we discovered that rs9624 showed an association with RA through an epistatic interaction with HLA-DRB1-11-Val. Overall, LAMPLINK showed high reliability for identifying epistatic genetic contributions hidden in complex traits.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"541-547"},"PeriodicalIF":2.6,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626919","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

Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati–Engelmann disease type II TGFB2 的潜伏相关肽域的紧身衣区的杂合突变导致卡姆拉蒂-恩格尔曼病 II 型。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-16 DOI: 10.1038/s10038-024-01274-1

Zheng Wang, Mitsuhiro Kometani, Leonid Zeitlin, Yael Wilnai, Akira Kinoshita, Koh-ichiro Yoshiura, Hiroko Ninomiya, Takeshi Imamura, Long Guo, Jingyi Xue, Li Yan, Hirofumi Ohashi, Yann Pretemer, Shunsuke Kawai, Masaaki Shiina, Kazuhiro Ogata, Daniel H. Cohn, Naomichi Matsumoto, Gen Nishimura, Junya Toguchida, Noriko Miyake, Shiro Ikegawa

{"title":"Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati–Engelmann disease type II","authors":"Zheng Wang, Mitsuhiro Kometani, Leonid Zeitlin, Yael Wilnai, Akira Kinoshita, Koh-ichiro Yoshiura, Hiroko Ninomiya, Takeshi Imamura, Long Guo, Jingyi Xue, Li Yan, Hirofumi Ohashi, Yann Pretemer, Shunsuke Kawai, Masaaki Shiina, Kazuhiro Ogata, Daniel H. Cohn, Naomichi Matsumoto, Gen Nishimura, Junya Toguchida, Noriko Miyake, Shiro Ikegawa","doi":"10.1038/s10038-024-01274-1","DOIUrl":"10.1038/s10038-024-01274-1","url":null,"abstract":"Camurati–Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 11","pages":"599-605"},"PeriodicalIF":2.6,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626918","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