Human molecular genetics最新文献

{"title":"KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome.","authors":"Amber S E van Oirsouw, Michael A Hadders, Martijn Koetsier, Edith D J Peters, Nurit Assia Batzir, Tahsin Stefan Barakat, Diana Baralle, Adelyn Beil, Marie-Noëlle Bonnet-Dupeyron, Philip M Boone, Arjan Bouman, Deanna Alexis Carere, Benjamin Cogne, Leslie Dunnington, Laura S Farach, Casie A Genetti, Bertrand Isidor, Louis Januel, Aakash Joshi, Nayana Lahiri, Kristen N Lee, Idit Maya, Meriel McEntagart, Hope Northrup, Mathilde Pujalte, Kate Richardson, Susan Walker, Bobby P C Koeleman, Mariëlle Alders, Richard H van Jaarsveld, Renske Oegema","doi":"10.1093/hmg/ddaf082","DOIUrl":"https://doi.org/10.1093/hmg/ddaf082","url":null,"abstract":"<p><p>Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150302","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":"Editor's Note: Naturally occurring germline and tumor-associated mutations within the ATP-binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53.","authors":"","doi":"10.1093/hmg/ddaf085","DOIUrl":"https://doi.org/10.1093/hmg/ddaf085","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150300","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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-26","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":"The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E.","authors":"Dennis O Pérez-López, Audrey A Shively, F Javier Llorente Torres, Roxanne Muchow, Zaid Abu-Salah, Mohammed T Abu-Salah, Jackson T Veltrop, Michael L Garcia, Catherine L Smith, D D W Cornelison, Nicole L Nichols, Monique A Lorson, Christian Lorson","doi":"10.1093/hmg/ddaf080","DOIUrl":"10.1093/hmg/ddaf080","url":null,"abstract":"<p><p>Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated two orthologous NEFLE396K mutation in the mouse C57BL/6 J background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing. Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142446","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":"Editor's Note to: Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.","authors":"","doi":"10.1093/hmg/ddaf086","DOIUrl":"https://doi.org/10.1093/hmg/ddaf086","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127534","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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-22","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":"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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-22","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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-21","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}

{"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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-18","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":"Calibrating a functional assay for variant classification in RYR1-related malignant hyperthermia susceptibility.","authors":"Evan Z Ying, Amber Douglass, Marwan A Hawari, Linda Groom, Kathryn Stowell, Robert T Dirksen, Jennifer J Johnston, Leslie G Biesecker","doi":"10.1093/hmg/ddaf038","DOIUrl":"10.1093/hmg/ddaf038","url":null,"abstract":"<p><strong>Purpose: </strong>Identifying individuals with pathogenic variants for RYR1-related Malignant Hyperthermia Susceptibility (MHS) could reduce morbidity and mortality due to MH reactions. Realization of this goal requires knowledge of variant pathogenicity, and proper weighting of functional assays is important for accurate variant classification. Caffeine-induced Ca2+ release assays can be used to support pathogenicity per the ClinGen Variant Curation Expert Panel (VCEP). However, the caffeine-induced Ca2+ release assay lacks formal validation with known pathogenic and benign variants.</p><p><strong>Methods: </strong>Fifteen benign/likely benign and six pathogenic/likely pathogenic RYR1 variants were used to calibrate the caffeine-induced Ca2+ release assay using a multi-mode microplate reader. Five variants of unknown significance (VUS) were assayed for possible reclassification.</p><p><strong>Results: </strong>Our data support use of the caffeine-induced Ca2+ release assay at a moderate weight per the American College of Medical Genetics and Genomics pathogenicity criteria schema with a positive likelihood ratio of 12.14:1 (pathogenicity) and a negative likelihood ratio of 0.22:1 (4.5:1 benignity). Using this validated assay, two of five VUS were reclassified as likely benign.</p><p><strong>Conclusion: </strong>Formal validation of the caffeine-induced Ca2+ release assay supports the VCEP functional criteria weighting at moderate strength based on these data. Additional variants should be assayed to shift more from VUS to benign or pathogenic classifications.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"945-951"},"PeriodicalIF":3.1,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795274","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}