Human molecular genetics最新文献

{"title":"Regulatory roles of rs2192932 and rs10487150 in autism spectrum disorder: insights from fine-mapping and cross-population validation.","authors":"Shuai Zhao, Haoxue Wang, Fang Hou, Yanlin Chen, Kaiheng Zhu, Rundong Liu, Zhen Xiang, Jiao Zhang, Xi Liang, Li Li, Ranran Song","doi":"10.1093/hmg/ddaf107","DOIUrl":"https://doi.org/10.1093/hmg/ddaf107","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence. GWAS have identified many ASD risk loci, but most are in non-coding regions, and the genetic value of nearby loci remains underexplored. We aim to conduct a fine-mapping analysis of ASD-associated SNPs and validate the signals across ethnic groups, focusing on their regulatory effects on gene expression. Variants within ±500 kb of known ASD loci were selected. Functional annotations were performed using RegulomeDB and CADD. ASD susceptibility genes were obtained from AutDB and SFARI, and screened for validation using 11 high-quality GEO datasets. eQTL analysis was conducted using GTEx database. For Chinese children, a case-control study design was adopted. Biological samples and demographic information were collected from 1244 children between 2010-2024. Extracted DNA was used for ASAMD chip. For European children, GWAS data from 46351 samples were obtained from iPSYCH-PGC-ASD project. 158 ASD susceptibility SNPs with cis-eQTL signals in brain tissue were identified. Notably, rs2192932 and rs10487150 showed consistent associations with ASD in both populations. In additive model, a G to A change at rs2192932 increased ASD risk by 29.5% (OR = 1.295, 95% CI: 1.046-1.605, P = 0.018), while an A to C change at rs10487150 increased risk by 22.7% (OR = 1.227, 95% CI: 1.008-1.495, P = 0.042). Additionally, rs2192932 and rs10487150 may influence ASD onset by regulating SERPINE1 expression. These findings offer new insights into the molecular genetics of ASD and support the potential of genetic markers for risk prediction and early screening.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674569","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}

{"title":"Pathogenic mutations disrupt stress granules assembly in patients with DDX3X neurodevelopmental disorder.","authors":"Yan Bi, Jingjing Sun, Decheng Ren, Xiaohui Gong, Lei Ji, Pei Lu, Fan Yuan, Yanlin Wang, Keyi Li, Lili Long, Guang He, Li Ma","doi":"10.1093/hmg/ddaf083","DOIUrl":"10.1093/hmg/ddaf083","url":null,"abstract":"<p><p>DDX3X neurodevelopmental disorder (DDX3X-NDD) represents a recently identified genetic syndrome characterized by intellectual disability (ID) and developmental delays, primarily caused by pathogenic variants in the DDX3X gene. The physiological ramifications of these mutations remain largely unexplored. In this study, we reported 21 DDX3X variants from 22 Chinese patients with DDX3X-NDD by whole exome sequencing. We selected five variants for further functional analyses, including two previously reported by our group. Three frameshift variants (c.280_281dup p.R95Efs*127, c.669_670del p.A224Pfs*70, and c.1579del p.H527Ifs*9) resulted in either the loss of DDX3X protein or the production of truncated proteins. Additionally, two missense variants (c.1051C > G p.R351G and c.1501G > A p.A501T) significantly reduced DDX3X protein expression. Notably, variants DDX3X-R95Efs*127 and DDX3X-A224Pfs*70 triggered marked apoptosis induction and failed to form stress granules in HEK293T cells compared to wild-type DDX3X. This defect may stem from their inability to interact with the stress particle marker PABPC1, as evidenced by co-immunoprecipitation assays. Moreover, DDX3X-H527Ifs*9 and DDX3X-R351G variants were found to disrupt the cell cycle, extending the S phase relative to the wild type. Collectively, our findings provide mechanistic insights into the pathogenic consequences of DDX3X-NDD associated mutations, suggesting that the loss-of-function variants of DDX3X lack a context-dependent survival advantage, potentially contributing to the pathology of this syndrome.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1328-1336"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142441","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}

{"title":"Correction to: ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function.","authors":"","doi":"10.1093/hmg/ddaf095","DOIUrl":"10.1093/hmg/ddaf095","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1337-1340"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309882","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}

{"title":"Correction to: TTC7A missense variants in intestinal disease can be classified by molecular and cellular phenotypes.","authors":"","doi":"10.1093/hmg/ddaf094","DOIUrl":"10.1093/hmg/ddaf094","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1342"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484093","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}

{"title":"Whole-exome sequencing identifies 5 novel genes associated with carpal tunnel syndrome.","authors":"Zi-Yi Wang, Xiao-Yu He, Bang-Sheng Wu, Liu Yang, Jia You, Wei-Shi Liu, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu","doi":"10.1093/hmg/ddaf076","DOIUrl":"10.1093/hmg/ddaf076","url":null,"abstract":"<p><p>Carpal tunnel syndrome (CTS), a common peripheral nerve entrapment disorder, has a high estimated heritability index. Although previous genome-wide association studies have assessed common genetic components of CTS, the risk contributed by coding variants is still not well understood. Here, we performed the largest exome-wide analyses using UK Biobank data from 350 770 participants to find coding variants associated with CTS. We then explored the relative contribution of both rare mutations and polygenic risk score (PRS) to CTS risk in survival analyses. Finally, we investigated the functional pathways of the CTS-related coding genes identified above. Aside from conforming 6 known CTS genes, 5 novel genes were identified (SPSB1, SYNC, ITGB5, MUC13 and LOXL4). The associations of most genes we identified with incident CTS were striking in survival analyses. Additionally, we provided evidence that combining rare coding alleles and polygenic risk score can improve the genetic prediction of CTS. Functional enrichment analyses revealed potential roles of the identified coding variants in CTS pathogenesis, where they contributed to extracellular matrix organization. Our results evaluated the contribution to CTS etiology from quantities of coding variants accessible to exome sequencing data.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1255-1264"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093476","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}

{"title":"Correction to: The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease.","authors":"","doi":"10.1093/hmg/ddaf112","DOIUrl":"10.1093/hmg/ddaf112","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1341"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484092","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}

{"title":"Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction.","authors":"Johanna Lehtonen, Anna H Hakonen, Antti Hassinen, Sanne Iversen Lurås, Meri Kaustio, Virpi Glumoff, Francisca Hinrichsen, Weiwei Li, Anna-Maija Sulonen, Sanna Wickman, Henrikki Almusa, Minttu Polso, Maarit Palomäki, Sirpa Kivirikko, Kristiina Avela, Kaarina Heiskanen, Vilja Pietiäinen, Kristiina Aittomäki, Janna Saarela","doi":"10.1093/hmg/ddaf081","DOIUrl":"10.1093/hmg/ddaf081","url":null,"abstract":"<p><p>Malformations of cortical development (MCDs) encompass a diverse group of genetic and clinical disorders. Here, we aimed to determine a genetic etiology for two siblings manifesting MCD, microcephaly, epilepsy, intellectual disability, and susceptibility to infections. A missense variant (NM_018084:c.929A > C, p.Asp310Ala) and an intragenic deletion (exons 14-16) in CCDC88A were identified as compound heterozygous in patients by genome sequencing. Truncating homozygous CCDC88A variants are known to cause an ultra-rare syndrome manifesting with MCD, microcephaly, seizures, and severe neurological impairment. CCDC88A encodes girdin, which is essential for various cell functions, such as actin remodeling and cell proliferation. Western blot analysis showed that the missense variant allele was expressed in fibroblasts at a level compatible with a heterozygous allele, whereas a truncated protein from the deletion allele was barely detectable. Proliferation and wound-healing assays revealed that girdin-deficient fibroblasts proliferated faster and migrated slower than controls. High-content imaging highlighted girdin-deficient fibroblasts as smaller and their actin remodeling disrupted, leading to perinuclear accumulation of endolysosomal organelles. To confirm these cellular phenotypes resulted from girdin loss, CRISPR-Cas9 edited knockout models of healthy fibroblasts were created, replicating the observations in patient cells. Additionally, the siblings exhibited reduced monocytoid and plasmacytoid dendritic cells, suggesting compromised immunity due to girdin deficiency. In summary, the study describes the first case of a CCDC88A missense variant and intragenic deletion associated with MCD. It demonstrates altered immunity and girdin-related cellular changes, such as cell morphology and proliferation-migration dichotomy, in patient and knockout fibroblasts, reinforcing the pathogenic relevance of these variants.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1294-1312"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119502","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}

{"title":"Expression of Concern: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.","authors":"","doi":"10.1093/hmg/ddaf104","DOIUrl":"10.1093/hmg/ddaf104","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1343"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511753","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}

{"title":"Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.","authors":"Neblina Sikta, Samuel Gooley, Timothy E Green, Olivia Hoeper, Tom Witkowski, Caitlin Bennett, David Francis, Joshua Reid, Kevin Mao, Mohammed Awad, Samuel Roberts-Thomson, Kristian Bulluss, Jonathan Clark, Ingrid E Scheffer, Piero Perucca, Mark F Bennett, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand","doi":"10.1093/hmg/ddaf077","DOIUrl":"10.1093/hmg/ddaf077","url":null,"abstract":"<p><p>Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1/CCM1 were found in 3/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4/7 individuals. These 4 individuals were from separate families with germline KRIT1/CCM1 variants. In 8/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1286-1293"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119527","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}

{"title":"The p.W651fsX666 mutation on COL10A1 results in impaired trimerization of normal collagen X to induce Schmid type Metaphyseal chondrodysplasia.","authors":"Jingye Yang, Jing Zhang, Qingxiang Lu, Haiying Tian, Ke Wang, Zhi Liu, Yu Xiong, Yadong Li, Ning Ma, Hongxia Tian, Zhongxue Zhou, Ding'an Zhou","doi":"10.1093/hmg/ddaf071","DOIUrl":"10.1093/hmg/ddaf071","url":null,"abstract":"<p><p>Haploinsufficiency resulting from the degradation of mutant Collagen Type X Alpha 1 Chain (COL10A1) mRNA by nonsense-mediated decay (NMD) has been attributed to the pathogenesis of Schmid-type metaphyseal chondrodysplasia (SMCD) in cases involving nonsense mutations. However, this mechanism does not fully explain the complexity of SMCD. In this study, we identified a c.1951_1952 InsT (p.W651 fsX666) mutation in exon 3 of COL10A1 that is associated with chondrodysplasia phenotypes in a two-generation family with SMCD. The mRNA decay of the mutant COL10A1 (named as affected E666X-COL10A1) is caused by the p.W651fsX666 mutation, which also disrupts the trimerization of normal collagen X. However, the mutant mRNA decay of affected exogenous E666X-COL10A1, as well as the complete degradation of E666X-COL10A1 mRNA in the proband, is not significantly induced by the W651fsX666 mutation. In vitro trimerization analyses results indicate that the trimerization of normal collagen X and wild-type collagen X are disrupted by W651fsX666 and E666X-collagen X mutations, respectively, suggesting that the mutant allele collagen X may impose a dominant-negative effect on the normal collagen X. Our results are the first to reveal that the impaired trimerization of normal collagen X is caused by the W651fsX666 mutation and a dominant-negative effect on the normal allele collagen X exerted by the mutant allele collagen X, causing impaired trimerization of collagen X, which will interpret the phenotype variability among the affected individuals in the pedigree with metaphyseal chondrodysplasia type Schmid (MCDS) studied.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1265-1285"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119528","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}