Journal of Human Genetics最新文献_第9页

Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7 小脑发育不全7（pontocellar hypoplasia 7）中核定位基序的TOE1变体的作用

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-04-11 DOI: 10.1038/s10038-024-01244-7

Yukiko Kuroda, Takuya Naruto, Yu Tsuyusaki, Ayumi Kato, Noriko Aida, Kenji Kurosawa

{"title":"Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7","authors":"Yukiko Kuroda, Takuya Naruto, Yu Tsuyusaki, Ayumi Kato, Noriko Aida, Kenji Kurosawa","doi":"10.1038/s10038-024-01244-7","DOIUrl":"10.1038/s10038-024-01244-7","url":null,"abstract":"Biallelic TOE1 variants can cause pontocerebellar hypoplasia type 7 (PCH7), a condition characterized by pontocerebellar hypoplasia with genital abnormality. TOE1 is a 3’-exonuclese for 3’-end maturation in small nuclear RNA. TOE1 pathogenic variants have been reported at the DEDD catalytic domain and zinc finger motif. Here, we describe a PCH7 patient with novel compound heterozygous TOE1 variants and a detailed clinical course. The patient was a 3-year-old female and showed developmental delay without cerebellar ataxic behavior. Head MRI revealed delayed myelination without pontocerebellar hypoplasia at 9 months of age. Progressive pontocerebellar atrophy was prominent at follow-up MRI. Cerebral abnormalities are characteristic features of PCH7 before pontocerebellar atrophy is observed. One variant, p.Arg331*, was located at the nuclear localization motif (NLM) and partially escaped from nonsense-mediated decay. This variant affected nuclear localization in mutant expressing cells, thus, the TOE1 variant at NLM leads to TOE1 dysfunction associated with nuclear mis-localization.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"349-355"},"PeriodicalIF":2.6,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140590772","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

Long-term course of a case with a novel homozygous kyphoscoliosis peptidase variant 一个患有新型同卵脊柱后凸肽酶变异的病例的长期病理过程

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-04-08 DOI: 10.1038/s10038-024-01250-9

Yohei Misumi, Taro Yamashita, Aki Kuratomi, Yoshitaka Murakami, Atsushi Fujita, Naomichi Matsumoto, Mitsuharu Ueda

引用次数: 0

Heritability of complex traits in sub-populations experiencing bottlenecks and growth 经历瓶颈和增长的亚种群复杂性状的遗传率

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-04-08 DOI: 10.1038/s10038-024-01249-2

Cameron S. Taylor, Daniel J. Lawson

{"title":"Heritability of complex traits in sub-populations experiencing bottlenecks and growth","authors":"Cameron S. Taylor, Daniel J. Lawson","doi":"10.1038/s10038-024-01249-2","DOIUrl":"10.1038/s10038-024-01249-2","url":null,"abstract":"Populations that have experienced a bottleneck are regularly used in Genome Wide Association Studies (GWAS) to investigate variants associated with complex traits. It is generally understood that these isolated sub-populations may experience high frequency of otherwise rare variants with large effect size, and therefore provide a unique opportunity to study said trait. However, the demographic history of the population under investigation affects all SNPs that determine the complex trait genome-wide, changing its heritability and genetic architecture. We use a simulation based approach to identify the impact of the demographic processes of drift, expansion, and migration on the heritability of complex trait. We show that demography has considerable impact on complex traits. We then investigate the power to resolve heritability of complex traits in GWAS studies subjected to demographic effects. We find that demography is an important component for interpreting inference of complex traits and has a nuanced impact on the power of GWAS. We conclude that demographic histories need to be explicitly modelled to properly quantify the history of selection on a complex trait.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"329-335"},"PeriodicalIF":2.6,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01249-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140590503","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 a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review 在一名患有脊柱骨发育不良症的中国胎儿中鉴定出一种新型 LFNG 变异并进行系统综述

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-04-02 DOI: 10.1038/s10038-024-01248-3

Lin Wang, Shuji Mizumoto, Ruixue Zhang, Yuqi Zhang, Yuan Liu, Wenjing Cheng, Xin Li, Min Dan, Chunyan Zhang, Xinru Gao, Juan Wang, Jiaqi Han, Lianying Jiao, Yating Wang, Qiujie Jin, Lihui Yang, Chenxing Li, Shuxian Li, Jinhui Zhu, Hai Jiang, Gen Nishimura, Takahiro Yamada, Shuhei Yamada, Na Cai, Rong Qiang, Long Guo

{"title":"Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review","authors":"Lin Wang, Shuji Mizumoto, Ruixue Zhang, Yuqi Zhang, Yuan Liu, Wenjing Cheng, Xin Li, Min Dan, Chunyan Zhang, Xinru Gao, Juan Wang, Jiaqi Han, Lianying Jiao, Yating Wang, Qiujie Jin, Lihui Yang, Chenxing Li, Shuxian Li, Jinhui Zhu, Hai Jiang, Gen Nishimura, Takahiro Yamada, Shuhei Yamada, Na Cai, Rong Qiang, Long Guo","doi":"10.1038/s10038-024-01248-3","DOIUrl":"10.1038/s10038-024-01248-3","url":null,"abstract":"Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"321-327"},"PeriodicalIF":2.6,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140590573","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

Correction: Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population 更正：动脉导管未闭（不包括 22q11.2 缺失综合征）的遗传学病因，以及在日本人群中发现 c.1617del，即 TMEM260 的一个流行变异。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-29 DOI: 10.1038/s10038-024-01245-6

Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

引用次数: 0

A mediation analysis framework based on variance component to remove genetic confounding effect 基于变异成分的中介分析框架可消除遗传混杂效应。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-03-25 DOI: 10.1038/s10038-024-01232-x

Zihan Dong, Hongyu Zhao, Andrew T. DeWan

{"title":"A mediation analysis framework based on variance component to remove genetic confounding effect","authors":"Zihan Dong, Hongyu Zhao, Andrew T. DeWan","doi":"10.1038/s10038-024-01232-x","DOIUrl":"10.1038/s10038-024-01232-x","url":null,"abstract":"Identification of pleiotropy at the single nucleotide polymorphism (SNP) level provides valuable insights into shared genetic signals among phenotypes. One approach to study these signals is through mediation analysis, which dissects the total effect of a SNP on the outcome into a direct effect and an indirect effect through a mediator. However, estimated effects from mediation analysis can be confounded by the genetic correlation between phenotypes, leading to inaccurate results. To address this confounding effect in the context of genetic mediation analysis, we propose a restricted-maximum-likelihood (REML)-based mediation analysis framework called REML-mediation, which can be applied to either individual-level or summary statistics data. Simulations demonstrated that REML-mediation provides unbiased estimates of the true cross-trait causal effect, assuming certain assumptions, albeit with a slightly inflated standard error compared to traditional linear regression. To validate the effectiveness of REML-mediation, we applied it to UK Biobank data and analyzed several mediator-outcome trait pairs along with their corresponding sets of pleiotropic SNPs. REML-mediation successfully identified and corrected for genetic confounding effects in these trait pairs, with correction magnitudes ranging from 7% to 39%. These findings highlight the presence of genetic confounding effects in cross-trait epidemiological studies and underscore the importance of accounting for them in data analysis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"301-309"},"PeriodicalIF":2.6,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288307","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

Visit to visit transition in TXNIP gene methylation and the risk of type 2 diabetes mellitus: a nested case-control study TXNIP 基因甲基化的逐次转换与 2 型糖尿病风险：一项巢式病例对照研究。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-03-25 DOI: 10.1038/s10038-024-01243-8

Yuying Wu, Weiling Chen, Yang Zhao, Minqi Gu, Yajuan Gao, Yamin Ke, Longkang Wang, Mengmeng Wang, Wenkai Zhang, Yaobing Chen, Weifeng Huo, Xueru Fu, Xi Li, Dongdong Zhang, Pei Qin, Fulan Hu, Yu Liu, Xizhuo Sun, Ming Zhang, Dongsheng Hu

{"title":"Visit to visit transition in TXNIP gene methylation and the risk of type 2 diabetes mellitus: a nested case-control study","authors":"Yuying Wu, Weiling Chen, Yang Zhao, Minqi Gu, Yajuan Gao, Yamin Ke, Longkang Wang, Mengmeng Wang, Wenkai Zhang, Yaobing Chen, Weifeng Huo, Xueru Fu, Xi Li, Dongdong Zhang, Pei Qin, Fulan Hu, Yu Liu, Xizhuo Sun, Ming Zhang, Dongsheng Hu","doi":"10.1038/s10038-024-01243-8","DOIUrl":"10.1038/s10038-024-01243-8","url":null,"abstract":"Our study aimed to investigate the association between the transition of the TXNIP gene methylation level and the risk of incident type 2 diabetes mellitus (T2DM). This study included 263 incident cases of T2DM and 263 matched non-T2DM participants. According to the methylation levels of five loci (CpG1–5; chr1:145441102-145442001) on the TXNIP gene, the participants were classified into four transition groups: maintained low, low to high, high to low, and maintained high methylation levels. Compared with individuals whose methylation level of CpG2–5 at the TXNIP gene was maintained low, individuals with maintained high methylation levels showed a 61–87% reduction in T2DM risk (66% for CpG2 [OR: 0.34, 95% CI: 0.14, 0.80]; 77% for CpG3 [OR: 0.23, 95% CI: 0.07, 0.78]; 87% for CpG4 [OR: 0.13, 95% CI: 0.03, 0.56]; and 61% for CpG5 [OR: 0.39, 95% CI: 0.16, 0.92]). Maintained high methylation levels of four loci of the TXNIP gene are associated with a reduction of T2DM incident risk in the current study. Our study suggests that preserving hypermethylation levels of the TXNIP gene may hold promise as a potential preventive measure against the onset of T2DM.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"311-319"},"PeriodicalIF":2.6,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288328","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

Correction: The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population 更正：日本普通人群中 BRCA1 和 BRCA2 变体的频率和致病性。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-14 DOI: 10.1038/s10038-024-01241-w

Masashi Idogawa, Tasuku Mariya, Yumi Tanaka, Tsuyoshi Saito, Hiroshi Nakase, Takashi Tokino, Akihiro Sakurai

引用次数: 0

Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies 扩展 TRAPPC9 和 MID2 相关神经发育障碍的遗传和表型谱：报告两种新型突变、三维建模和分子对接研究。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-03-11 DOI: 10.1038/s10038-024-01242-9

Marwa Kharrat, Chahnez Triki, Abir ben isaa, Wafa Bouchaala, Olfa Alila, Jihen Chouchen, Yosra Ghouliya, Fatma Kamoun, Abdelaziz Tlili, Faiza Fakhfakh

{"title":"Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies","authors":"Marwa Kharrat, Chahnez Triki, Abir ben isaa, Wafa Bouchaala, Olfa Alila, Jihen Chouchen, Yosra Ghouliya, Fatma Kamoun, Abdelaziz Tlili, Faiza Fakhfakh","doi":"10.1038/s10038-024-01242-9","DOIUrl":"10.1038/s10038-024-01242-9","url":null,"abstract":"Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 7","pages":"291-299"},"PeriodicalIF":2.6,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101731","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

New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder 对与 MADD 相关的神经发育障碍的临床和分子谱的新认识。

IF 3.5 3区生物学

Journal of Human Genetics Pub Date : 2024-03-08 DOI: 10.1038/s10038-024-01236-7

Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid

{"title":"New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder","authors":"Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid","doi":"10.1038/s10038-024-01236-7","DOIUrl":"10.1038/s10038-024-01236-7","url":null,"abstract":"Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD-related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 6","pages":"263-270"},"PeriodicalIF":3.5,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01236-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065255","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