Human Genetics最新文献_第2页

Integrating transcriptomic and polygenic risk scores to enhance predictive accuracy for ischemic stroke subtypes. 整合转录组学和多基因风险评分，提高缺血性中风亚型的预测准确性。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-18 DOI: 10.1007/s00439-024-02717-7

Xuehong Cai, Haochang Li, Xiaoxiao Cao, Xinyan Ma, Wenhao Zhu, Lei Xu, Sheng Yang, Rongbin Yu, Peng Huang

{"title":"Integrating transcriptomic and polygenic risk scores to enhance predictive accuracy for ischemic stroke subtypes.","authors":"Xuehong Cai, Haochang Li, Xiaoxiao Cao, Xinyan Ma, Wenhao Zhu, Lei Xu, Sheng Yang, Rongbin Yu, Peng Huang","doi":"10.1007/s00439-024-02717-7","DOIUrl":"https://doi.org/10.1007/s00439-024-02717-7","url":null,"abstract":"Ischemic stroke (IS), characterized by complex etiological diversity, is a significant global health challenge. Recent advancements in genome-wide association studies (GWAS) and transcriptomic profiling offer promising avenues for enhanced risk prediction and understanding of disease mechanisms. GWAS summary statistics from the GIGASTROKE Consortium and genetic and phenotypic data from the UK Biobank (UKB) were used. Transcriptome-Wide Association Studies (TWAS) were conducted using FUSION to identify genes associated with IS and its subtypes across eight tissues. Colocalization analysis identified shared genetic variants influencing both gene expression and disease risk. Sum Transcriptome-Polygenic Risk Scores (STPRS) models were constructed by combining polygenic risk scores (PRS) and polygenic transcriptome risk scores (PTRS) using logistic regression. The predictive performance of STPRS was evaluated using the area under the curve (AUC). A Phenome-wide association study (PheWAS) explored associations between STPRS and various phenotypes. TWAS identified 34 susceptibility genes associated with IS and its subtypes. Colocalization analysis revealed 18 genes with a posterior probability (PP) H4 > 75% for joint expression quantitative trait loci (eQTL) and GWAS associations, highlighting their genetic relevance. The STPRS models demonstrated superior predictive accuracy compared to conventional PRS, showing significant associations with numerous UKB phenotypes, including atrial fibrillation and blood pressure. Integrating transcriptomic data with polygenic risk scores through STPRS enhances predictive accuracy for IS and its subtypes. This approach refines our understanding of the genetic and molecular landscape of stroke and paves the way for tailored preventive and therapeutic strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647531","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}

引用次数: 0

Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity. 对转录组和蛋白质组广泛关联研究的综合分析确定了肥胖症功能基因的优先次序。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-04 DOI: 10.1007/s00439-024-02714-w

Qi-Gang Zhao, Xin-Ling Ma, Qian Xu, Zi-Tong Song, Fan Bu, Kuan Li, Bai-Xue Han, Shan-Shan Yan, Lei Zhang, Yuan Luo, Yu-Fang Pei

{"title":"Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity.","authors":"Qi-Gang Zhao, Xin-Ling Ma, Qian Xu, Zi-Tong Song, Fan Bu, Kuan Li, Bai-Xue Han, Shan-Shan Yan, Lei Zhang, Yuan Luo, Yu-Fang Pei","doi":"10.1007/s00439-024-02714-w","DOIUrl":"https://doi.org/10.1007/s00439-024-02714-w","url":null,"abstract":"Background: Genome-wide association studies have identified dozens of genomic loci for obesity. However, functional genes and their detailed genetic mechanisms underlying these loci are mainly unknown. In this study, we conducted an integrative study to prioritize plausibly functional genes by combining information from genome-, transcriptome- and proteome-wide association analyses.Methods: We first conducted proteome-wide association analyses and transcriptome-wide association analyses for the six obesity-related traits. We then performed colocalization analysis on the identified loci shared between the proteome- and transcriptome-association analyses. Finally, we validated the identified genes with other plasma/blood reference panels. The highlighted genes were assessed for expression of other tissues, single-cell and tissue specificity, and druggability.Results: We prioritized 4 high-confidence genes (FASN, ICAM1, PDCD6IP, and YWHAB) by proteome-wide association studies, transcriptome-wide association studies, and colocalization analyses, which consistently influenced the variation of obesity traits at both mRNA and protein levels. These 4 genes were successfully validated using other plasma/blood reference panels. These 4 genes shared regulatory structures in obesity-related tissues. Single-cell and tissue-specific analyses showed that FASN and ICAM1 were explicitly expressed in metabolism- and immunity-related tissues and cells. Furthermore, FASN and ICAM1 had been developed as drug targets.Conclusion: Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568057","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}

引用次数: 0

Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease. 脊髓小脑共济失调 3 型/马加多-约瑟夫病患者血液和口腔拭子 DNA 中 ATXN3 CAG 重复的体细胞扩增与年龄有关。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-08 DOI: 10.1007/s00439-024-02698-7

Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton

{"title":"Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease.","authors":"Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton","doi":"10.1007/s00439-024-02698-7","DOIUrl":"10.1007/s00439-024-02698-7","url":null,"abstract":"Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease onset and slowing the rate of somatic expansion has been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define the number and sequence of the ATXN3 repeat, the genotype of an adjacent single nucleotide variant and quantify somatic expansion in blood and buccal swab DNA of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1363-1378"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390202","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}

引用次数: 0

VCAT: an integrated variant function annotation tools. VCAT：综合变异功能注释工具。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI: 10.1007/s00439-024-02699-6

Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao

{"title":"VCAT: an integrated variant function annotation tools.","authors":"Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao","doi":"10.1007/s00439-024-02699-6","DOIUrl":"10.1007/s00439-024-02699-6","url":null,"abstract":"The development of sequencing technology has promoted discovery of variants in the human genome. Identifying functions of these variants is important for us to link genotype to phenotype, and to diagnose diseases. However, it usually requires researchers to visit multiple databases. Here, we presented a one-stop webserver for variant function annotation tools (VCAT, https://biomed.nscc-gz.cn/zhaolab/VCAT/ ) that is the first one connecting variant to functions via the epigenome, protein, drug and RNA. VCAT is also the first one to make all annotations visualized in interactive charts or molecular structures. VCAT allows users to upload data in VCF format, and download results via a URL. Moreover, VCAT has annotated a huge number (1,262,041,068) of variants collected from dbSNP, 1000 Genomes projects, gnomAD, ICGC, TCGA, and HPRC Pangenome project. For these variants, users are able to searcher their functions, related diseases and drugs from VCAT. In summary, VCAT provides a one-stop webserver to explore the potential functions of human genomic variants including their relationship with diseases and drugs.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1311-1322"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080183","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}

引用次数: 0

GBF1 deficiency causes cataracts in human and mouse. GBF1 缺乏会导致人类和小鼠白内障。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-07 DOI: 10.1007/s00439-024-02697-8

Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang

{"title":"GBF1 deficiency causes cataracts in human and mouse.","authors":"Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang","doi":"10.1007/s00439-024-02697-8","DOIUrl":"10.1007/s00439-024-02697-8","url":null,"abstract":"Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1281-1291"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897333","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}

引用次数: 0

Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients. 在近亲结婚的先天性心脏病患者中发现罕见的同源纤毛基因变异。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1007/s00439-024-02703-z

Daniel A Baird, Hira Mubeen, Canan Doganli, Jasmijn B Miltenburg, Oskar Kaaber Thomsen, Zafar Ali, Tahir Naveed, Asif Ur Rehman, Shahid Mahmood Baig, Søren Tvorup Christensen, Muhammad Farooq, Lars Allan Larsen

{"title":"Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients.","authors":"Daniel A Baird, Hira Mubeen, Canan Doganli, Jasmijn B Miltenburg, Oskar Kaaber Thomsen, Zafar Ali, Tahir Naveed, Asif Ur Rehman, Shahid Mahmood Baig, Søren Tvorup Christensen, Muhammad Farooq, Lars Allan Larsen","doi":"10.1007/s00439-024-02703-z","DOIUrl":"10.1007/s00439-024-02703-z","url":null,"abstract":"Congenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a CHD risk factor in Asian populations with a high degree of consanguineous marriages. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology. To obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patient's malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patient's coding genome by whole exome sequencing. The patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P < 2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P < 5.4e-04) and the 23 candidate disease genes (P < 5.2e-04). Functional investigation of ADCY6 in cell- and zebrafish-models verified its role in heart development. Our results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1323-1339"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345798","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}

引用次数: 0

Methodologies underpinning polygenic risk scores estimation: a comprehensive overview. 多基因风险分数估算的基础方法：全面概述。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-19 DOI: 10.1007/s00439-024-02710-0

Carene Anne Alene Ndong Sima, Kathryn Step, Yolandi Swart, Haiko Schurz, Caitlin Uren, Marlo Möller

{"title":"Methodologies underpinning polygenic risk scores estimation: a comprehensive overview.","authors":"Carene Anne Alene Ndong Sima, Kathryn Step, Yolandi Swart, Haiko Schurz, Caitlin Uren, Marlo Möller","doi":"10.1007/s00439-024-02710-0","DOIUrl":"10.1007/s00439-024-02710-0","url":null,"abstract":"Polygenic risk scores (PRS) have emerged as a promising tool for predicting disease risk and treatment outcomes using genomic data. Thousands of genome-wide association studies (GWAS), primarily involving populations of European ancestry, have supported the development of PRS models. However, these models have not been adequately evaluated in non-European populations, raising concerns about their clinical validity and predictive power across diverse groups. Addressing this issue requires developing novel risk prediction frameworks that leverage genetic characteristics across diverse populations, considering host-microbiome interactions and a broad range of health measures. One of the key aspects in evaluating PRS is understanding the strengths and limitations of various methods for constructing them. In this review, we analyze strengths and limitations of different methods for constructing PRS, including traditional weighted approaches and new methods such as Bayesian and Frequentist penalized regression approaches. Finally, we summarize recent advances in PRS calculation methods development, and highlight key areas for future research, including development of models robust across diverse populations by underlining the complex interplay between genetic variants across diverse ancestral backgrounds in disease risk as well as treatment response prediction. PRS hold great promise for improving disease risk prediction and personalized medicine; therefore, their implementation must be guided by careful consideration of their limitations, biases, and ethical implications to ensure that they are used in a fair, equitable, and responsible manner.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1265-1280"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464152","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}

引用次数: 0

Genotypic and phenotypic correlations in tooth agenesis: insights from WNT10A and EDA mutations in syndromic and non-syndromic forms. 牙齿缺失的基因型和表型相关性：综合征和非综合征中 WNT10A 和 EDA 基因突变的启示。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-09-25 DOI: 10.1007/s00439-024-02705-x

Youmei Wu, Ling Lai, Junyang Chen, Xinzhu Li, Jin Hou

引用次数: 0

Integrative genomic analyses identify neuroblastoma risk genes involved in neuronal differentiation. 整合基因组分析确定了参与神经元分化的神经母细胞瘤风险基因。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI: 10.1007/s00439-024-02700-2

Matilde Tirelli, Ferdinando Bonfiglio, Sueva Cantalupo, Annalaura Montella, Marianna Avitabile, Teresa Maiorino, Sharon J Diskin, Achille Iolascon, Mario Capasso

{"title":"Integrative genomic analyses identify neuroblastoma risk genes involved in neuronal differentiation.","authors":"Matilde Tirelli, Ferdinando Bonfiglio, Sueva Cantalupo, Annalaura Montella, Marianna Avitabile, Teresa Maiorino, Sharon J Diskin, Achille Iolascon, Mario Capasso","doi":"10.1007/s00439-024-02700-2","DOIUrl":"10.1007/s00439-024-02700-2","url":null,"abstract":"Genome-Wide Association Studies (GWAS) have been decisive in elucidating the genetic predisposition of neuroblastoma (NB). The majority of genetic variants identified in GWAS are found in non-coding regions, suggesting that they can be causative of pathogenic dysregulations of gene expression. Nonetheless, pinpointing the potential causal genes within implicated genetic loci remains a major challenge. In this study, we integrated NB GWAS and expression Quantitative Trait Loci (eQTL) data from adrenal gland to identify candidate genes impacting NB susceptibility. We found that ZMYM1, CBL, GSKIP and WDR81 expression was dysregulated by NB predisposing variants. We further investigated the functional role of the identified genes through computational analysis of RNA sequencing (RNA-seq) data from single-cell and whole-tissue samples of NB, neural crest, and adrenal gland tissues, as well as through in vitro differentiation assays in NB cell cultures. Our results indicate that dysregulation of ZMYM1, CBL, GSKIP, WDR81 may lead to malignant transformation by affecting early and late stages of normal program of neuronal differentiation. Our findings enhance the understanding of how specific genes contribute to NB pathogenesis by highlighting their influence on neuronal differentiation and emphasizing the impact of genetic risk variants on the regulation of genes involved in critical biological processes.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1293-1309"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080182","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}

引用次数: 0

Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis. ERLIN1的双倍变体：13例痉挛性截瘫患者的系列研究。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-04 DOI: 10.1007/s00439-024-02702-0

Guillaume Cogan, Maha S Zaki, Mahmoud Issa, Boris Keren, Marine Guillaud-Bataille, Florence Renaldo, Arnaud Isapof, Pauline Lallemant, Giovanni Stevanin, Lena Guillot-Noel, Thomas Courtin, Julien Buratti, Cécile Freihuber, Joseph G Gleeson, Robyn Howarth, Alexandra Durr, Jean-Madeleine de Sainte Agathe, Cyril Mignot

{"title":"Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.","authors":"Guillaume Cogan, Maha S Zaki, Mahmoud Issa, Boris Keren, Marine Guillaud-Bataille, Florence Renaldo, Arnaud Isapof, Pauline Lallemant, Giovanni Stevanin, Lena Guillot-Noel, Thomas Courtin, Julien Buratti, Cécile Freihuber, Joseph G Gleeson, Robyn Howarth, Alexandra Durr, Jean-Madeleine de Sainte Agathe, Cyril Mignot","doi":"10.1007/s00439-024-02702-0","DOIUrl":"10.1007/s00439-024-02702-0","url":null,"abstract":"Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1353-1362"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375343","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}

引用次数: 0