Journal of Human Genetics最新文献

英文中文

Augmenting cost-effectiveness in clinical diagnosis using extended whole-exome sequencing: SNVs, SVs, and beyond 使用扩展全外显子组测序提高临床诊断的成本效益：snv， SVs等。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-08 DOI: 10.1038/s10038-025-01403-4

Fuyuki Miya, Daisuke Nakato, Hisato Suzuki, Mamiko Yamada, Daisuke Watanabe, Toshiki Takenouchi, Kenjiro Kosaki

In standard short-read whole-exome sequencing (WES), capture probes are typically designed to target the protein-coding regions (CDS), and regions outside the exons—except for adjacent intronic sequences—are rarely sequenced. Although the majority of known pathogenic variants reside within the CDS as nonsynonymous variants, some disease-causing variants are located in regions that are difficult to detect by WES alone, such as deep intronic variants and structural variants, often requiring whole-genome sequencing (WGS) for detection. Moreover, WES has limitations in reliably identifying pathogenic variants within mitochondrial DNA or repetitive regions. Here, we propose a strategy to improve the diagnostic yield in a cost-effective manner by expanding the target design of WES beyond the CDS. As an illustrative example, we experimentally validated an extended WES approach covering intronic and untranslated regions (UTRs) of 188 genes listed in the Japanese public health insurance-covered multiple gene testing, intronic and UTRs of 81 genes listed in ACMG Secondary Findings (SF) v3.2, and 70 repeat regions associated with diseases. Additionally, the entire mitochondrial genome was targeted. We demonstrate the coverage of these extended regions based on experimental data and present case examples in which previously diagnosed pathogenic variants located outside the CDS were successfully detected using this approach. This strategy enables a substantial increase in the chance of achieving a definitive diagnosis for patients using WES alone, without requiring WGS, at a cost comparable to conventional WES. Our method has the potential to significantly shorten the diagnostic odyssey and represents a valuable approach in clinical genomics.

在标准的短读全外显子组测序（WES）中，捕获探针通常被设计用于靶向蛋白质编码区（CDS），而外显子区域（除了相邻的内含子序列）很少被测序。虽然大多数已知的致病变异作为非同义变异存在于CDS中，但一些致病变异位于仅通过WES难以检测的区域，例如深层内含子变异和结构变异，通常需要全基因组测序（WGS）进行检测。此外，WES在可靠地识别线粒体DNA或重复区域内的致病变异方面存在局限性。在这里，我们提出了一种策略，通过将WES的目标设计扩展到CDS之外，以经济有效的方式提高诊断率。为了举例说明，我们通过实验验证了一种扩展的WES方法，该方法涵盖了日本公共健康保险覆盖的多基因检测中列出的188个基因的内含子和非翻译区（UTRs）， ACMG Secondary Findings (SF) v3.2中列出的81个基因的内含子和非翻译区，以及70个与疾病相关的重复区域。此外，整个线粒体基因组都是目标。我们根据实验数据证明了这些扩展区域的覆盖范围，并提出了使用这种方法成功检测到位于CDS外的先前诊断的致病变异的病例示例。这一策略大大增加了单独使用WES而不需要WGS的患者获得明确诊断的机会，其成本与传统WES相当。我们的方法具有显著缩短诊断过程的潜力，代表了临床基因组学的一种有价值的方法。

{"title":"Augmenting cost-effectiveness in clinical diagnosis using extended whole-exome sequencing: SNVs, SVs, and beyond","authors":"Fuyuki Miya, Daisuke Nakato, Hisato Suzuki, Mamiko Yamada, Daisuke Watanabe, Toshiki Takenouchi, Kenjiro Kosaki","doi":"10.1038/s10038-025-01403-4","DOIUrl":"10.1038/s10038-025-01403-4","url":null,"abstract":"In standard short-read whole-exome sequencing (WES), capture probes are typically designed to target the protein-coding regions (CDS), and regions outside the exons—except for adjacent intronic sequences—are rarely sequenced. Although the majority of known pathogenic variants reside within the CDS as nonsynonymous variants, some disease-causing variants are located in regions that are difficult to detect by WES alone, such as deep intronic variants and structural variants, often requiring whole-genome sequencing (WGS) for detection. Moreover, WES has limitations in reliably identifying pathogenic variants within mitochondrial DNA or repetitive regions. Here, we propose a strategy to improve the diagnostic yield in a cost-effective manner by expanding the target design of WES beyond the CDS. As an illustrative example, we experimentally validated an extended WES approach covering intronic and untranslated regions (UTRs) of 188 genes listed in the Japanese public health insurance-covered multiple gene testing, intronic and UTRs of 81 genes listed in ACMG Secondary Findings (SF) v3.2, and 70 repeat regions associated with diseases. Additionally, the entire mitochondrial genome was targeted. We demonstrate the coverage of these extended regions based on experimental data and present case examples in which previously diagnosed pathogenic variants located outside the CDS were successfully detected using this approach. This strategy enables a substantial increase in the chance of achieving a definitive diagnosis for patients using WES alone, without requiring WGS, at a cost comparable to conventional WES. Our method has the potential to significantly shorten the diagnostic odyssey and represents a valuable approach in clinical genomics.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 1","pages":"13-21"},"PeriodicalIF":2.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular genetics and therapeutic development for GNE myopathy. GNE肌病的分子遗传学和治疗进展。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-05 DOI: 10.1038/s10038-025-01398-y

Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino

GNE myopathy is an autosomal recessive distal myopathy resulting from biallelic pathogenic variants in the GNE gene, a key enzyme in sialic acid biosynthesis. Although most pathogenic variants are missense variants, recent advances have enabled the identification of copy number variations, deep intronic variants, and regulatory changes in the promoter region, significantly enhancing diagnostic accuracy. Progress in genetic diagnostics now allows detection of rare and complex variants. Studies of founder variants in specific populations have clarified that certain GNE genotypes are associated with distinct clinical features and disease progression, deepening our understanding of genotype-phenotype relationships in GNE myopathy. The development of approved therapies, such as aceneuramic acid extended-release tablets, as well as ongoing multicenter Phase 2 trials of ManNAc and promising pilot studies of 6'-sialyllactose, underscore the importance of timely and comprehensive genetic diagnosis. Additional approaches, including antioxidant and gene therapies, are also under investigation. Since genetic testing is currently the sole definitive diagnostic approach, continued efforts to identify challenging or novel variants are essential to ensure all affected individuals receive an accurate diagnosis and access to emerging therapies. Advances in molecular genetics and diagnostics are paving the way for precision medicine and improved outcomes in GNE myopathy.

GNE肌病是一种常染色体隐性远端肌病，由唾液酸生物合成的关键酶GNE基因的双等位致病变异引起。虽然大多数致病变异是错义变异，但最近的进展已经能够识别拷贝数变异、深层内含子变异和启动子区域的调节变化，显著提高了诊断的准确性。遗传诊断的进步现在可以检测到罕见和复杂的变异。对特定人群中奠基者变异的研究表明，某些GNE基因型与不同的临床特征和疾病进展相关，加深了我们对GNE肌病基因型-表型关系的理解。已获批准的治疗方法的发展，如乙酰胆酸缓释片，以及正在进行的ManNAc多中心ii期试验和有希望的6'-唾液酰基乳糖试点研究，都强调了及时和全面的遗传诊断的重要性。包括抗氧化和基因治疗在内的其他方法也在研究中。由于基因检测是目前唯一确定的诊断方法，因此继续努力识别具有挑战性或新颖的变异对于确保所有受影响的个体获得准确的诊断和获得新兴疗法至关重要。分子遗传学和诊断学的进步为精确医学和改善GNE肌病的预后铺平了道路。

{"title":"Molecular genetics and therapeutic development for GNE myopathy.","authors":"Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino","doi":"10.1038/s10038-025-01398-y","DOIUrl":"https://doi.org/10.1038/s10038-025-01398-y","url":null,"abstract":"<p><p>GNE myopathy is an autosomal recessive distal myopathy resulting from biallelic pathogenic variants in the GNE gene, a key enzyme in sialic acid biosynthesis. Although most pathogenic variants are missense variants, recent advances have enabled the identification of copy number variations, deep intronic variants, and regulatory changes in the promoter region, significantly enhancing diagnostic accuracy. Progress in genetic diagnostics now allows detection of rare and complex variants. Studies of founder variants in specific populations have clarified that certain GNE genotypes are associated with distinct clinical features and disease progression, deepening our understanding of genotype-phenotype relationships in GNE myopathy. The development of approved therapies, such as aceneuramic acid extended-release tablets, as well as ongoing multicenter Phase 2 trials of ManNAc and promising pilot studies of 6'-sialyllactose, underscore the importance of timely and comprehensive genetic diagnosis. Additional approaches, including antioxidant and gene therapies, are also under investigation. Since genetic testing is currently the sole definitive diagnostic approach, continued efforts to identify challenging or novel variants are essential to ensure all affected individuals receive an accurate diagnosis and access to emerging therapies. Advances in molecular genetics and diagnostics are paving the way for precision medicine and improved outcomes in GNE myopathy.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Congenital disorders caused by aberrations in the biosynthesis of chondroitin/dermatan sulfate. 由软骨素/硫酸皮肤素生物合成异常引起的先天性疾病。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-02 DOI: 10.1038/s10038-025-01396-0

Tadahisa Mikami, Shuji Mizumoto, Hiroshi Kitagawa, Shuhei Yamada

Chondroitin sulfate (CS)/dermatan sulfate (DS) proteoglycans that play indispensable roles in multiple physiological processes, including cell proliferation, cell adhesion, development, neuronal guidance, and cartilage formation. Depletion of CS/DS caused by biosynthetic enzyme loss of function impairs these processes and results in embryonic lethality. However, some individuals with mutant enzymes survive and exhibit severe phenotypes. These rare hereditary diseases have been discovered and characterized in recent decades because of marked advances in next-generation sequencing technology. In this review, CS/DS-related inherited diseases caused by aberrations in both CS/DS backbone synthesis, as well as their sulfation and/or epimerization, are comprehensively summarized and their pathogenesis discussed.

硫酸软骨素(CS)/硫酸皮肤聚糖（DS）蛋白聚糖在细胞增殖、细胞粘附、发育、神经元引导和软骨形成等多种生理过程中发挥着不可或缺的作用。由生物合成酶功能丧失引起的CS/DS耗竭会损害这些过程并导致胚胎致死。然而，一些具有突变酶的个体存活下来并表现出严重的表型。近几十年来，由于下一代测序技术的显著进步，这些罕见的遗传性疾病已经被发现和表征。本文综述了由CS/DS主链合成异常及其硫酸化和/或外聚异构化引起的CS/DS相关遗传病的研究进展，并对其发病机制进行了探讨。

引用次数: 0

A novel MCMDC2 variant causes meiotic arrest and non-obstructive azoospermia in a consanguineous Chinese family 一种新的MCMDC2变异在一个近亲中国家庭中引起减数分裂停止和非阻塞性无精子症。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-02 DOI: 10.1038/s10038-025-01397-z

Qi Fang, Lanxi Ran, Song Liu, Jianyong Di, Ye Liu, Fengqin Xu, Binbin Wang

Non-obstructive azoospermia (NOA) is often associated with genetic variants. Whole-exome sequencing (WES) has emerged as a powerful tool in studying the genetic diagnosis of NOA and to help identify novel causal gene variants. Minichromosome maintenance domain-containing 2 (MCMDC2), an atypical yet conserved MCM protein, plays a key role in meiotic recombination and the maintenance of fertility. To date, only a limited number of MCMDC2 variants have been reported. The current study identified a novel deleterious variant (c.G226T/p.Val76Phe) of MCMDC2 by WES in a patient with NOA from a consanguineous Chinese family. Bioinformatics analysis indicated that the altered amino acid is highly conserved, and the c.G226T/p.Val76Phe variant may affect the structure and function of the MCMDC2 protein. Our results provide new insights into the underlying etiology of NOA in humans, further expanding the mutant spectrum of MCMDC2.

非阻塞性无精子症（NOA）通常与遗传变异有关。全外显子组测序（WES）已成为研究NOA遗传诊断和帮助识别新的致病基因变异的有力工具。小染色体维持结构域2 （MCMDC2）是一种非典型但保守的MCM蛋白，在减数分裂重组和维持生育能力中起关键作用。迄今为止，仅报道了有限数量的MCMDC2变异。目前的研究在来自中国近亲家庭的NOA患者中通过WES发现了MCMDC2的一种新的有害变异（c.G226T/p.Val76Phe）。生物信息学分析表明，改变的氨基酸具有高度保守性，c.G226T/p。Val76Phe变异可能影响MCMDC2蛋白的结构和功能。我们的研究结果为人类NOA的潜在病因提供了新的见解，进一步扩大了MCMDC2的突变谱。

引用次数: 0

MYH2-associated myopathy caused by novel compound heterozygous mutations: a case report and literature review 新型复合杂合突变引起的myh2相关肌病1例报告及文献复习

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-01 DOI: 10.1038/s10038-025-01400-7

Yulai Kang, Tong Yang, Xue Chen, Zhuo Min, Chunhua Tang, Lili Zhang, Lu Guo

MYH2-associated myopathy is a group of congenital heterogeneous diseases. Case reports with MYH2-associated myopathy due to compound heterozygous mutations are rare. We report a 63-year-old Asian female who presented with bilateral ptosis and limb weakness for over 10 years. The orbits magnetic resonance imaging showed no abnormalities. Muscle biopsy revealed characteristics consistent with congenital neuromuscular disease with uniform type 1 fibers. Genetic testing identified compound heterozygous mutations in the MYH2 gene: a heterozygous mutation in exon 30, c.4066G>T (chr17:10430037, p.E1356X) and a heterozygous mutation in exon 38, c.5473-1G>A (chr17:10426730, splicing). The novel gene mutations are considered potential pathogenic variants. MYH2-associated myopathy was diagnosed. Following treatment with cytidine diphosphate choline, coenzyme Q10, methylcobalamin, and idebenone, her ocular symptoms showed slight improvement before discharge. This case highlights the importance of genetic testing in diagnosing rare myopathies and expands the genetic spectrum of MYH2-associated myopathy.

myh2相关肌病是一组先天性异质性疾病。病例报告与myh2相关的肌病由于复合杂合突变是罕见的。我们报告了一位63岁的亚洲女性，她表现为双侧上睑下垂和肢体无力超过10年。眼眶核磁共振未见异常。肌肉活检显示的特征与先天性神经肌肉疾病一致，1型纤维均匀。基因检测在MYH2基因中发现了复合杂合突变：外显子30 c.4066G> a杂合突变（chr17:10430037, p.E1356X）和外显子38 c.5473-1G> a杂合突变（chr17:10426730，剪接）。新的基因突变被认为是潜在的致病变异。诊断为myh2相关肌病。经胞苷二磷酸胆碱、辅酶Q10、甲基钴胺素和依地苯酮治疗，出院前眼部症状略有改善。本病例强调了基因检测在诊断罕见肌病中的重要性，并扩大了myh2相关肌病的遗传谱。

{"title":"MYH2-associated myopathy caused by novel compound heterozygous mutations: a case report and literature review","authors":"Yulai Kang, Tong Yang, Xue Chen, Zhuo Min, Chunhua Tang, Lili Zhang, Lu Guo","doi":"10.1038/s10038-025-01400-7","DOIUrl":"10.1038/s10038-025-01400-7","url":null,"abstract":"MYH2-associated myopathy is a group of congenital heterogeneous diseases. Case reports with MYH2-associated myopathy due to compound heterozygous mutations are rare. We report a 63-year-old Asian female who presented with bilateral ptosis and limb weakness for over 10 years. The orbits magnetic resonance imaging showed no abnormalities. Muscle biopsy revealed characteristics consistent with congenital neuromuscular disease with uniform type 1 fibers. Genetic testing identified compound heterozygous mutations in the MYH2 gene: a heterozygous mutation in exon 30, c.4066G>T (chr17:10430037, p.E1356X) and a heterozygous mutation in exon 38, c.5473-1G>A (chr17:10426730, splicing). The novel gene mutations are considered potential pathogenic variants. MYH2-associated myopathy was diagnosed. Following treatment with cytidine diphosphate choline, coenzyme Q10, methylcobalamin, and idebenone, her ocular symptoms showed slight improvement before discharge. This case highlights the importance of genetic testing in diagnosing rare myopathies and expands the genetic spectrum of MYH2-associated myopathy.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"655-659"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of two novel pathogenic mutations in the SKOR2 gene linked to cerebellar hypoplasia and a broad spectrum of neurodevelopmental delay in two Iranian families 鉴定与两个伊朗家庭小脑发育不全和广谱神经发育迟缓相关的两个新的SKOR2基因致病性突变。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-01 DOI: 10.1038/s10038-025-01399-x

Mohammad Ali Farazi Fard, Zahra Tabatabaei, Mobarakeh Ajam-Hosseini, Pooneh Nikuei, Fatemeh Gila, Farshid Parvini, Payman Jamali

SKOR2 is a transcriptional repressor expressed in central nervous system tissues, mainly in the Purkinje cells (PCs). This is essential for the proper migration, development, and differentiation of PCs at embryonic stages, and its disruption can affect cerebellar function. SKOR2 protein has two DHD and SAND domains, which play an important role in the TGF-β signaling pathway by binding to Smad transcriptional regulators. Herein, we report nine patients from two unrelated Iranian families suffering from a distinctive combination of learning disability, facial dysmorphisms, and motor and speech impairments. Whole exome sequencing (WES) was employed to identify pathogenic variants in the probands. Sanger sequencing was conducted to confirm the mutations found in the patients, their healthy parents, and relatives. A range of bioinformatics tools was utilized to assess the impact of the identified mutations on the function and structure of the related proteins. WES identified two novel missense (c.374 G > C: p.Arg125Pro) and frameshift (c.1271_1274del: p.K424Rfs*71) mutations in exon 2 of the SKOR2 gene. After segregation and in-silico studies, autosomal recessive inheritance and pathogenic nature of the identified mutation were confirmed. In addition, the studied patients had distinct phenotypes such as clumsiness, dysarthria, and severe hypotonia compared to previous studies, which we named Skor2-related syndrome. These findings indicated a novel SKOR2-related syndrome characterized by neurodevelopmental delay and ataxia. Our findings, given the limited previous studies on the SKOR2 gene, expanded the pathogenic mutations and phenotypic spectrum of SKOR2-associated disorders, provided criteria facilitating early diagnosis and supported genetic counseling for prognosis and family planning.

SKOR2是一种在中枢神经系统组织中表达的转录抑制因子，主要在浦肯野细胞（PCs）中表达。这对于PCs在胚胎阶段的正常迁移、发育和分化至关重要，其破坏会影响小脑功能。SKOR2蛋白具有两个DHD和SAND结构域，通过与Smad转录调控因子结合，在TGF-β信号通路中发挥重要作用。在此，我们报告了来自两个不相关的伊朗家庭的9名患者，他们患有学习障碍、面部畸形、运动和语言障碍的独特组合。采用全外显子组测序（WES）鉴定先证者的致病变异。进行Sanger测序以确认在患者、其健康父母和亲属中发现的突变。利用一系列生物信息学工具来评估鉴定的突变对相关蛋白的功能和结构的影响。WES在SKOR2基因的外显子2上发现了两个新的错义突变（C .374 G > C: p.a g125pro）和移码突变（C .1271_1274del: p.K424Rfs*71）。经过分离和芯片研究，证实了所鉴定突变的常染色体隐性遗传和致病性。此外，与以往的研究相比，研究的患者具有明显的表型，如笨拙，构音障碍和严重的张力低下，我们将其命名为skor2相关综合征。这些发现提示了一种以神经发育迟缓和共济失调为特征的新型skor2相关综合征。鉴于以往对SKOR2基因的研究有限，我们的研究结果扩大了SKOR2相关疾病的致病突变和表型谱，为早期诊断提供了标准，并为预后和计划生育提供了遗传咨询。

{"title":"Identification of two novel pathogenic mutations in the SKOR2 gene linked to cerebellar hypoplasia and a broad spectrum of neurodevelopmental delay in two Iranian families","authors":"Mohammad Ali Farazi Fard, Zahra Tabatabaei, Mobarakeh Ajam-Hosseini, Pooneh Nikuei, Fatemeh Gila, Farshid Parvini, Payman Jamali","doi":"10.1038/s10038-025-01399-x","DOIUrl":"10.1038/s10038-025-01399-x","url":null,"abstract":"SKOR2 is a transcriptional repressor expressed in central nervous system tissues, mainly in the Purkinje cells (PCs). This is essential for the proper migration, development, and differentiation of PCs at embryonic stages, and its disruption can affect cerebellar function. SKOR2 protein has two DHD and SAND domains, which play an important role in the TGF-β signaling pathway by binding to Smad transcriptional regulators. Herein, we report nine patients from two unrelated Iranian families suffering from a distinctive combination of learning disability, facial dysmorphisms, and motor and speech impairments. Whole exome sequencing (WES) was employed to identify pathogenic variants in the probands. Sanger sequencing was conducted to confirm the mutations found in the patients, their healthy parents, and relatives. A range of bioinformatics tools was utilized to assess the impact of the identified mutations on the function and structure of the related proteins. WES identified two novel missense (c.374 G > C: p.Arg125Pro) and frameshift (c.1271_1274del: p.K424Rfs*71) mutations in exon 2 of the SKOR2 gene. After segregation and in-silico studies, autosomal recessive inheritance and pathogenic nature of the identified mutation were confirmed. In addition, the studied patients had distinct phenotypes such as clumsiness, dysarthria, and severe hypotonia compared to previous studies, which we named Skor2-related syndrome. These findings indicated a novel SKOR2-related syndrome characterized by neurodevelopmental delay and ataxia. Our findings, given the limited previous studies on the SKOR2 gene, expanded the pathogenic mutations and phenotypic spectrum of SKOR2-associated disorders, provided criteria facilitating early diagnosis and supported genetic counseling for prognosis and family planning.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"635-643"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterozygous PRDM9 truncating variant in a patient with primary ovarian insufficiency 原发性卵巢功能不全患者的杂合子PRDM9截断变异。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-08-29 DOI: 10.1038/s10038-025-01394-2

Abdelkader Heddar, Juliette Fievez, Radoslava Saraeva, Thibaut Benquey, Guillaume Jouret

引用次数: 0

Biallelic TSEN2 variants causing pontocerebellar hypoplasia type 2 双等位基因TSEN2变异导致桥小脑发育不全2型。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-08-27 DOI: 10.1038/s10038-025-01393-3

Yukina Hayashi, Keisuke Hamada, Kavitha Rethanavelu, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Kazuhiro Ogata, Atsushi Fujita, Naomichi Matsumoto

Pontocerebellar hypoplasia type 2 (PCH2) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in tRNA splicing endonuclease (TSEN) subunit genes. Variants in TSEN54 are most common, with very few cases of TSEN2-related PCH2B reported to date. Here, we report a 7-year-old girl with typical PCH2 features, including progressive microcephaly, epilepsy, developmental delay, cerebellar atrophy, and dystonia. Exome sequencing revealed compound heterozygous TSEN2 variants, a known missense variant NM_025265.4:c.926A>G p.(Tyr309Cys) and a novel nonsense variant c.1048C>T p.(Arg350*). Structural modeling suggested that p.(Tyr309Cys) moderately destabilizes the TSEN2–TSEN54 interface, while p.(Arg350*) truncates the catalytic domain. Despite a minor predicted impact on structure, p.(Tyr309Cys) was associated with severe clinical symptoms in both homozygous and compound heterozygous states. This study expands the TSEN2 mutation spectrum and highlights the utility of integrating structural modeling with clinical data to refine genotype–phenotype correlations in PCH2B.

桥小脑发育不全2型（PCH2）是由tRNA剪接内切酶（TSEN）亚基基因双等位致病变异引起的常染色体隐性神经退行性疾病。TSEN54的变异最为常见，迄今为止报道的与tsen2相关的PCH2B病例很少。在这里，我们报告一个7岁的女孩，具有典型的PCH2特征，包括进行性小头畸形、癫痫、发育迟缓、小脑萎缩和肌张力障碍。外显子组测序显示复合杂合TSEN2变异，已知错义变异NM_025265.4:c。926A>G p.（Tyr309Cys）和新的无义变体c.1048C >t p.（Arg350*）。结构模型表明p.（Tyr309Cys）适度破坏了TSEN2-TSEN54界面的稳定性，而p.（Arg350*）截断了催化结构域。尽管预测p.（Tyr309Cys）对结构的影响很小，但在纯合和复合杂合状态下，p.（Tyr309Cys）都与严重的临床症状相关。本研究扩展了TSEN2突变谱，并强调了将结构建模与临床数据相结合以完善PCH2B基因型-表型相关性的实用性。

{"title":"Biallelic TSEN2 variants causing pontocerebellar hypoplasia type 2","authors":"Yukina Hayashi, Keisuke Hamada, Kavitha Rethanavelu, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Kazuhiro Ogata, Atsushi Fujita, Naomichi Matsumoto","doi":"10.1038/s10038-025-01393-3","DOIUrl":"10.1038/s10038-025-01393-3","url":null,"abstract":"Pontocerebellar hypoplasia type 2 (PCH2) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in tRNA splicing endonuclease (TSEN) subunit genes. Variants in TSEN54 are most common, with very few cases of TSEN2-related PCH2B reported to date. Here, we report a 7-year-old girl with typical PCH2 features, including progressive microcephaly, epilepsy, developmental delay, cerebellar atrophy, and dystonia. Exome sequencing revealed compound heterozygous TSEN2 variants, a known missense variant NM_025265.4:c.926A>G p.(Tyr309Cys) and a novel nonsense variant c.1048C>T p.(Arg350*). Structural modeling suggested that p.(Tyr309Cys) moderately destabilizes the TSEN2–TSEN54 interface, while p.(Arg350*) truncates the catalytic domain. Despite a minor predicted impact on structure, p.(Tyr309Cys) was associated with severe clinical symptoms in both homozygous and compound heterozygous states. This study expands the TSEN2 mutation spectrum and highlights the utility of integrating structural modeling with clinical data to refine genotype–phenotype correlations in PCH2B.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"649-654"},"PeriodicalIF":2.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disease-specific genetic diagnostic strategies for muscle diseases unresolved by short-read sequencing. 短读测序未解决的肌肉疾病特异性遗传诊断策略。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-08-26 DOI: 10.1038/s10038-025-01391-5

Yoshihiko Saito, Ichizo Nishino

In recent years, whole-exome and whole-genome sequencing have been increasingly applied for the genetic diagnosis of muscle diseases. However, standard short-read sequencing often fails to detect pathogenic variants in some inherited muscle diseases, such as Duchenne/Becker muscular dystrophy (DMD/BMD), facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and oculopharyngodistal myopathy (OPDM). This review outlines the genetic diagnostic approaches for these conditions, with a particular focus on novel analytical approaches for genetic diagnosis.

近年来，全外显子组和全基因组测序越来越多地应用于肌肉疾病的遗传诊断。然而，标准的短读测序往往无法检测到一些遗传性肌肉疾病的致病变异，如Duchenne/Becker肌营养不良症（DMD/BMD）、面肩肱肌营养不良症（FSHD）、眼咽肌营养不良症（OPMD）和眼咽远端肌病（OPDM）。这篇综述概述了这些条件的遗传诊断方法，特别侧重于遗传诊断的新分析方法。

引用次数: 0

A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant 日本家族性痉挛性截瘫与错义UBQLN2变异相关。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-08-22 DOI: 10.1038/s10038-025-01392-4

Kazuki Watanabe, Tatsuya Ema, Kenji Shimizu, Kosuke Yamada, Mitsuko Nakashima, Hirotomo Saitsu

UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.

UBQLN2位于Xp11.21上，编码参与蛋白稳态的泛素2蛋白。UBQLN2的杂合子或半合子错义变异导致肌萎缩性侧索硬化症（ALS）。此外，罕见的原发性侧索硬化症（PLS）和痉挛性截瘫（SPG）与UBQLN2变异相关的病例也有报道。在这里，我们报告了四名患有SPG家族的男性患者携带半合子错义UBQLN2变异（NM_013444.4:c）。1442 g > T, p。(Gly481Val))。这些患者表现为儿童期开始的下肢痉挛，进展为步态障碍。平均发病年龄（11岁）早于既往ALS（49.6岁）、SPG（29岁）和PLS（25.5岁）病例，进展速度慢于ALS或PLS。文献回顾显示Pro506错义变异与多种运动神经元疾病表型相关，部分SPG患者进展为ALS。因此，我们认为对ubqln2相关的SPG患者进行仔细的随访是必要的。

引用次数: 0

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Journal of Human Genetics

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀