Journal of Human Genetics最新文献

{"title":"Molecular genetics of myotonic dystrophy and the evolution of therapeutic approaches.","authors":"Joe Nemoto, Masayuki Nakamori","doi":"10.1038/s10038-025-01358-6","DOIUrl":"10.1038/s10038-025-01358-6","url":null,"abstract":"<p><p>Myotonic dystrophy (DM) is the most common form of adult-onset muscular dystrophy, characterized by skeletal muscle symptoms such as myotonia and progressive muscle wasting, alongside a wide array of multisystemic manifestations affecting the cardiovascular, gastrointestinal, central nervous, endocrine, and ocular systems. DM is an autosomal dominant disorder caused by the unstable expansion of non-coding repeat sequences within the disease-causative genes. The mutant transcripts harboring these expanded repeats exert pathogenic effects via a toxic gain-of-function mechanism, most notably through RNA mediated toxicity that perturbs alternative splicing regulation and contributes to the diverse clinical phenotype. Beyond splicing defects, aberrant signal transduction and the activation of cellular senescence pathways have also been implicated in disease pathophysiology. This review summarizes current understanding of the molecular genetics and mechanistic basis of DM, outlines recent progress in therapeutic development-particularly RNA-targeted strategies involving nucleic acid-based therapeutics and small molecules-and explores emerging approaches aimed at modulating repeat expansions as a means to mitigate disease progression.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553701","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}

{"title":"A novel USP27X missense variant identified in an individual with intellectual disability.","authors":"Sukun Luo, Meng Zhang, Xiankai Zhang, Yufeng Huang, Li Tan, Peiwei Zhao, Hongmin Zhu, Xuelian He","doi":"10.1038/s10038-025-01359-5","DOIUrl":"https://doi.org/10.1038/s10038-025-01359-5","url":null,"abstract":"<p><p>X-linked intellectual disability (XLID) is a group of neurodevelopmental disorders with genetic heterogeneity. Mutation of USP27X, a deubiquitinase encoding gene, is associated with X-linked intellectual developmental disorder-105 (XLID105), which is characterized by different combinations of impaired intellectual development (ID), developmental delay (DD), autism spectrum, attention deficit hyperactivity disorder and anxiety. Now only fourteen genetically diagnosed individuals have been reported. Here we describe a three-year boy with mild abnormal facial features, DD, severe speech delay and cognitive impairment, and ventricular septal defect. In addition, an increased nuchal translucency was observed during the fetal period. Trio whole-exome sequencing identified a novel missense variant, c.257 C > T (p.Thr86Met), in the USP27X gene (NM_001145073), which is inherited from his healthy mother and assessed to be a variant of uncertain significance. Further in vitro function study shows that this variant is detrimental to the expression and deubiquitination activity of USP27X. Our study provides more pathogenic evidences for this variant identified, and link this variant to the XLID-105 disease. In conclusion, our report expands the clinical and genetic spectrum of USP27X. Clinical trial registration: ChiCTR2000034358.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540502","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}

{"title":"Molecular genetics of dystrophinopathy.","authors":"Mariko Okubo","doi":"10.1038/s10038-025-01357-7","DOIUrl":"https://doi.org/10.1038/s10038-025-01357-7","url":null,"abstract":"<p><p>Dystrophinopathies, including Duchenne and Becker muscular dystrophies, are caused by pathogenic variants in the DMD gene, which spans 2.5 Mb and encodes multiple tissue-specific dystrophin isoforms. Advances in molecular diagnostic techniques have expanded our ability to detect a broad spectrum of DMD variants, including exonic deletions/duplications, small variants such as single-nucleotide variants and indels, and intronic rearrangements that disrupt splicing. Transcriptomic and long-read genomic analyses have revealed previously undetectable mechanisms of variation, including pseudoexon inclusion, intronic polyadenylation, and repeat expansions, underscoring the importance of integrating RNA-level data and in silico predictions into diagnostics. Genotype-phenotype correlations are influenced by the type and location of variants and by other factors, such as naturally occurring exon skipping and modifier genes. For instance, partial dystrophin expression caused by exon skipping in patients with certain nonsense variants can result in a milder Becker-like phenotype. These findings highlight the clinical significance of functional assays, such as minigene splicing reporters and immunostaining, in refining variant interpretation. This review summarizes the spectrum of DMD variants and outlines a stepwise diagnostic approach that integrates genetic, transcriptomic, and computational data. Special consideration is given to subgroups, such as female carriers and patients with mild phenotypes, in whom molecular diagnosis can be particularly challenging. Although therapeutic strategies are not the primary focus of this article, accurate molecular diagnosis forms the foundation for guiding individualized care. Together, these insights emphasize the value of integrated multi-omic variant assessment in improving diagnostic accuracy and patient management for dystrophinopathies.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540504","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}

{"title":"Approaches to diagnostic screening for congenital disorders of glycosylation and its prevalence in Japan.","authors":"Nobuhiko Okamoto, Machiko Kadoya, Yoshinao Wada","doi":"10.1038/s10038-025-01362-w","DOIUrl":"https://doi.org/10.1038/s10038-025-01362-w","url":null,"abstract":"<p><p>Congenital disorders of glycosylation (CDG) represent an emerging and significant category within the spectrum of inborn errors of metabolism. CDG comprise a heterogeneous group of diseases caused by defects at various stages of the glycosylation pathway. Each year, new types of CDG are identified, and to date, pathogenic variants in 189 genes have been associated with over 200 distinct human glycosylation-related disorders. Each type of CDG exhibits characteristic clinical features. Many of CDG result in multisystem involvement, with the central nervous system being particularly affected. Clinical manifestations are highly variable and may include developmental delays, growth impairment, neurological abnormalities such as ataxia, hepatic dysfunction, cardiac defects, coagulation disorders, and abnormal fat distribution. In patients with unexplained neurological symptoms, it is now standard practice to include CDG in the differential diagnosis. Detection of altered glycosylation patterns in serum proteins is essential in the diagnostic evaluation of CDG. Analytical techniques allow the identification of defects in N-glycosylation, O-glycosylation, and combined glycosylation pathways. Once abnormalities in glycosylation are detected, subsequent genetic analysis is necessary to identify causative variants. Our research institute has contributed to the CDG diagnostic support center in Japan by developing novel analytical methods utilizing mass spectrometry. Through these efforts, we have facilitated the molecular diagnosis of 66 patients with CDG across Japan. In this report, we provide an overview of the current landscape of CDG in Japan, along with a summary of the screening and diagnostic processes.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540503","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}

{"title":"A copy number variant overlapping the 3'UTR of PLP1 causes spastic paraplegia.","authors":"Malak Alghamdi, Essa Alharbi, Salman Aljarallah, Ghaida Alghamdi, Reham M Balahmar, Nisserin Jado, Hebattalah Hamed, Dima Jamjoom, Fahad A Bashiri, Naif A M Almontashiri","doi":"10.1038/s10038-025-01340-2","DOIUrl":"10.1038/s10038-025-01340-2","url":null,"abstract":"<p><p>Leukodystrophy presents a significant diagnostic challenge due to its varied clinical presentation and similarity to other myelin disorders, characterized by abnormalities in myelin and white matter. Hypomyelination disorders, including Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegias (SPG), are associated with variants in the proteolipid protein 1 (PLP1) gene, leading to symptoms ranging from severe dysmyelination in infancy to delayed dysmyelination and axonal degeneration in adulthood. Family history was taken, and pedigree was constructed. Recruitment included seven males and females with spastic paraplegia and nine healthy relatives, who were clinically investigated, and tested with molecular genetic assays including whole exome sequencing (WES), whole genome sequencing (WGS), and PCR amplification with fragment analysis on gel electrophoresis to identify and confirm the genetic cause. Family history was consistent with hereditary condition marked by progressive spastic paraplegia in 10 family members. Males had early onset and progressive paraplegia, and neurodegenerative conditions, resulting in a decline in the neurocognitive functions. However, in some females, the symptoms manifested later in their 30s-40s, leading to neurodegenerative conditions and spastic paraplegias. A total of 16 family members were available for genetic testing and segregation studies. Initial clinical WES in four members was negative. Next, WGS identified a novel copy number variant (CNV) loss (75.5 kb) involving the 3'UTR of the PLP1 gene in three members (the mother, affected son, but not in the unaffected son). Segregation studies in all 16 family members confirmed the presence of the CNV in five additional affected individuals and an asymptomatic female, but not in the eight asymptomatic individuals. Our study reports a novel 3'UTR CNV in PLP1 in a large family with several individuals affected with SPG. This finding expands the mutational landscape of the PLP1-related diseases to include CNV and, possibly, small sequence changes in the regulatory regions of PLP1, that would otherwise be overlooked during the interpretation of the next generation sequencing data.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"365-370"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811478","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}

{"title":"Variant sub-tiering, disease-gene associations and strictness of clinical criteria improves the interpretation of variants of uncertain significance in hereditary cardiomyopathies and rhythm disorders.","authors":"Marco Castori, Sandra Mastroianno, Andrea Fontana, Silvia Morlino, Grazia Nardella, Ester Di Muro, Pietro Palumbo, Maria Pia Leone, Riccardo Pracella, Orazio Palumbo, Antonio Petracca, Domenico Rosario Potenza, Massimo Carella, Giovanni De Luca, Carlo Coli, Raimondo Salvatore Massaro, Rosa De Santis, Lorenzo Vaccaro, Marcella Cesana, Davide Cacchiarelli, Massimiliano Copetti, Carmela Fusco, Giuseppe Di Stolfo","doi":"10.1038/s10038-025-01344-y","DOIUrl":"10.1038/s10038-025-01344-y","url":null,"abstract":"<p><p>Besides the ClinGen's efforts to standardize the ACMG/AMP criteria and European initiatives aimed at monitoring quality standards, molecular diagnostics of hereditary cardiomyopathies and heart rhythm disorders (HCHRDs) remains strongly influenced by the local strategies developed to overcome the variables in which genetic testing is requested. This is a monocentric study on the clinical and molecular findings of 363 pedigrees with various HCHRDs. ACMG/AMP criteria were adapted according to the ClinGen's material and internal specifications. Phenotypes were reviewed according to known disease-gene associations and the concurrence of multiple variants in the same individual. Relatives were studied when available and the significance of selected variants was supported by RNA- studies before reporting. One or more (likely) pathogenic variants were found in 80 pedigrees (22.0%), while 96 (26.4%) displayed one or more variants of uncertain significance (VUS) only. The 132 identified VUS were sub-tiered according to the Bayesian score in three categories presenting distinguishable patterns of selected criteria. VUS_high showed profiles of key molecular criteria and resembled deleterious variants according to the combinations of assigned criteria, while the VUS_low category displayed a high chance of conflicting combinations of criteria and unsupported disease-gene associations. Reclassification to likely pathogenic by the application of applicable clinical criteria (PVS1_Strength, PP1 and PP4) was accessible to VUS_high and a few VUS_mid only. This work supports the combined need to (i) introduce VUS sub-tiering, (ii) consider known disease-gene associations, (iii) stringently apply clinical criteria and (iv) incorporate RNA data to improve the clinical significance of genetic testing in HCHRDs.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"349-358"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994829","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}

{"title":"GPD1 deficiency-a rare, overlooked cause of liver disease.","authors":"Necati Emrecan Türk, Serkan Belkaya, Selçuk Teke, Ceyda Tuna Kırsaçlıoğlu, Fatma Tuba Eminoğlu, Tunahan Çalıkoğlu, Aydan Kansu, Zarife Kuloglu","doi":"10.1038/s10038-025-01339-9","DOIUrl":"10.1038/s10038-025-01339-9","url":null,"abstract":"<p><p>Transient infantile hypertriglyceridemia is one of the diseases that should be considered in case of unexplained elevated liver enzymes, hypertriglyceridemia and hepatosteatosis. We report 2 siblings with novel homozygous variants in the GPD1 gene with transient infantile hypertriglyceridemia. Two siblings born from consanguineous marriage were referred due to hepatomegaly, elevated transaminases and fatty liver. After excluding other possible causes of fatty liver and elevated transaminase levels; whole-exome sequencing (WES) was performed on genomic DNA isolated from the peripheral blood samples of both patients. Whole exome sequencing revealed the identification of a novel homozygous variant, c.628 G > C:p.G210R, in GPD1. Our report underscores the importance of genome sequencing in diagnosing unexplained childhood fatty liver disease and/or elevated enzyme levels. In patients with transient infantile hypertriglyceridemia, investigation into novel homozygous variants in the GPD1 gene should be conducted using whole exome sequencing.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"375-379"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969627","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}

{"title":"Regulation of MCCC1 expression by a Parkinson's disease-associated intronic variant: implications for pathogenesis.","authors":"Shunsaku Sogabe, Hiroko Nakano, Yusuke Ogasahara, Pei-Chieng Cha, Yuko Ando, Mariko Taniguchi-Ikeda, Ryusaku Matsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Shigeo Murayama, Takashi Aoi, Tatsushi Toda, Wataru Satake","doi":"10.1038/s10038-025-01335-z","DOIUrl":"10.1038/s10038-025-01335-z","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. While some familial cases result from single-gene mutations, most are sporadic, involving complex genetic and environmental interactions. Among PD risk loci identified through genome-wide association studies, MCCC1 encodes a mitochondrial enzyme essential for leucine catabolism; however, the causal variant remains unclear. Here, we investigated whether the intronic variant rs12637471 regulates MCCC1 mRNA expression and influences PD risk. Postmortem brain analysis revealed significantly elevated MCCC1 mRNA levels in G-allele carriers, consistent with peripheral tissue eQTL data from GTEx. Using CRISPR/Cas9-edited induced pluripotent stem cells, we generated isogenic lines differing only at rs12637471 and observed increased MCCC1 expression in G-allele dopaminergic neurons. Given MCCC1's mitochondrial role, its dysregulation may impact mitochondrial homeostasis, autophagy, or inflammation, potentially contributing to PD pathogenesis.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"371-374"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988309","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}

{"title":"Hemizygous SMARCA1 variants cause X-linked intellectual disability.","authors":"Naoto Nishimura, Takeshi Mizuguchi, Keisuke Hamada, Kotaro Yuge, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Yoriko Watanabe, Hitoshi Osaka, Koh-Ichiro Yoshiura, Kazuhiro Ogata, Naomichi Matsumoto","doi":"10.1038/s10038-025-01346-w","DOIUrl":"10.1038/s10038-025-01346-w","url":null,"abstract":"<p><p>Pathogenic SNF2 related chromatin remodeling ATPase 1 (SMARCA1) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel SMARCA1 variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous SMARCA1 variant (NM_003069.5:c.1795 C > T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G > T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between SMARCA1 and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing SMARCA1 function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"359-363"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985295","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}

{"title":"Elevated serum autotaxin levels and multiple system atrophy-like presentation in a patient with PLA2G6-associated neurodegeneration.","authors":"So Okubo, Takashi Matsukawa, Norifumi Kawamoto, Masahiko Tsujita, Kenta Orimo, Hiroya Naruse, Jun Mitsui, Masashi Hamada, Wataru Satake, Tatsushi Toda","doi":"10.1038/s10038-025-01342-0","DOIUrl":"10.1038/s10038-025-01342-0","url":null,"abstract":"<p><p>PLA2G6-associated neurodegeneration (PLAN) encompasses a spectrum of phenotypes caused by biallelic pathogenic variants in PLA2G6. Initially linked to infantile and atypical neuroaxonal dystrophy, PLAN now includes adult-onset conditions such as dystonia-parkinsonism, ataxia, and spastic paraplegia. We report a female patient presenting young-onset parkinsonism with pyramidal tract signs, cerebellar atrophy, and autonomic dysfunction, mimicking multiple system atrophy (MSA). Neuroimaging showed decreased dopamine uptake and cerebellar hypoperfusion. Genetic analysis identified a homozygous pathogenic variant in PLA2G6 (c.967G>A, p.Val323Met), confirming a diagnosis of PLAN. Interestingly, elevated serum autotaxin levels (4.67 ng/mL) without liver abnormalities. Bilateral brachymetatarsia was also observed, which may indicate an association with the PLA2G6 variant. This case underscores the importance of considering PLAN in cases of young-onset parkinsonism with multisystem involvement. Genetic testing is crucial for accurate diagnosis and management of such cases. Elevated serum autotaxin levels may be associated with decreased phospholipase activity in PLAN and warrants further investigation.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"381-384"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024130","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}