Journal of Human Genetics最新文献_第2页

Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction. 新生儿肝功能不全患者新型和复发性RINT1变异的功能分析。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-09-12 DOI: 10.1038/s10038-025-01404-3

Taiga Aoki, Ayano Inui, Yoshiyasu Ogata, Arisa Igarashi, Kumiko Yanagi, Masahiko Yamamori, Takaya Iida, Yoshihiro H Inoue, Yoichi Matsubara, Tadashi Kaname

{"title":"Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction.","authors":"Taiga Aoki, Ayano Inui, Yoshiyasu Ogata, Arisa Igarashi, Kumiko Yanagi, Masahiko Yamamori, Takaya Iida, Yoshihiro H Inoue, Yoichi Matsubara, Tadashi Kaname","doi":"10.1038/s10038-025-01404-3","DOIUrl":"https://doi.org/10.1038/s10038-025-01404-3","url":null,"abstract":"Rad50-interacting protein (RINT1) interacts with the endoplasmic reticulum (ER) tethering and SNARE complex, playing a central role in membrane trafficking and lipid metabolism. Loss-of-function variants of RINT1 have been related to episodic severe transaminitis with skeletal dysplasia or spastic paraplegia. We report two unrelated patients with recurrent markedly elevated aminotransferase triggered by fever, accompanied by coagulopathy and hyperammonemia. Liver biopsy revealed liver steatosis and bridging fibrosis in one patient, while the other displayed mild hepatocyte enlargement. Trio-whole-exome sequencing identified biallelic pathogenic RINT1 variants in the two patients. A novel missense variant [c.662 A > C, p.(His221Pro)] and a recurrent splice-site variant (c.1333+1 G > A) were identified in the first case. In the second case, a recurrent pathogenic RINT1 homozygous missense variant [c.1102 G > A, p.(Ala368Thr)] was identified. We investigated the pathogenicity of these variants through immunoprecipitation. Recombinant proteins produced from the mutant RINT1 transcript (p.His221Pro or p.Ala368Thr) displayed disrupted ER tether and SNARE interactions. Since the inhibition of ER-Golgi transport is associated with ER-stress activation, unfolded protein response (UPR)-related gene expression was investigated by qPCR. TIP20, a RINT1 homolog in Saccharomyces cerevisiae, is needed for autophagosome formation; therefore, an LC3-II turnover assay was performed and revealed disrupted autophagic flux. In addition, we created a fat-body-specific Rint1 knockdown in Drosophila. In the mutant larva, tissue atrophy and decreased lipid droplets in the fat body were observed. These results indicated that a loss of RINT1 function activated the UPR, impairs autophagy, and led to lipid storage abnormalities, contributing to the pathogenesis of liver disease.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054034","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

Whole exome sequencing in Japanese spinocerebellar ataxia identifies novel variants. 日本脊髓小脑共济失调的全外显子组测序鉴定出新的变异。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-09-12 DOI: 10.1038/s10038-025-01405-2

Tomoaki Watanabe, Kodai Kume, Ken Inoue, Masataka Nakamura, Shinji Yamamoto, Takashi Kurashige, Tomohiko Ohshita, Taku Tazuma, Misako Kaido, Yuta Maetani, Hirofumi Maruyama, Hideshi Kawakami

{"title":"Whole exome sequencing in Japanese spinocerebellar ataxia identifies novel variants.","authors":"Tomoaki Watanabe, Kodai Kume, Ken Inoue, Masataka Nakamura, Shinji Yamamoto, Takashi Kurashige, Tomohiko Ohshita, Taku Tazuma, Misako Kaido, Yuta Maetani, Hirofumi Maruyama, Hideshi Kawakami","doi":"10.1038/s10038-025-01405-2","DOIUrl":"https://doi.org/10.1038/s10038-025-01405-2","url":null,"abstract":"Spinocerebellar degeneration (SCD) is a clinically and genetically diverse group, and the dominant form of SCD (AD-SCD) is generally referred to as spinocerebellar ataxia (SCA) that primarily affects the cerebellum. Some patients do not have a definitive genetic diagnosis but may carry unknown variants of known causative genes. Here, we screened for known SCA-associated genes in patients with suspected SCA. We examined 174 patients with SCA lacking abnormal repeat expansion of known causative genes. Whole-exome sequencing (WES) was performed to screen for variants in SCA-associated genes. The identified variants were confirmed by Sanger sequencing, and their pathogenicity was determined using five web-based algorithms. WES revealed novel single-nucleotide variants (SNVs) in three genes, ELOVL4, ELOVL5, and GRM1. Patients presented with symptoms other than cerebellar symptoms. One patient with an ELOVL4 variant exhibited skin changes, a typical symptom of ELOVL4 SCA, whereas the other ELOVL4 SCA patient had no skin changes and exhibited mild parkinsonism and calcification in the globus pallidus and dentate nucleus. The patient with an ELOVL5 variant exhibited bladder and rectal disturbances. Finally, patients with GRM1 variants showed few common features beyond the cerebellar symptoms. One patient showed white matter lesions, cognitive decline, and no-no head tremors, whereas the other showed spasticity. The identification of novel SNVs in these known SCA-associated genes will expand our understanding of the genetic landscape of SCA and facilitate the diagnosis of previously undiagnosed patients.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054098","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

Germline pathogenic variants detected by GenMineTOP: insight from a nationwide tumor/normal paired comprehensive genomic profiling test, in Japan. GenMineTOP检测的种系致病变异：来自日本全国肿瘤/正常配对综合基因组分析测试的见解。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-09-09 DOI: 10.1038/s10038-025-01389-z

Eri Habano, Miho Ogawa, Kousuke Watanabe, Nana Akiyama, Hyangri Chang, Mirei Ka, Aya Shinozaki-Ushiku, Masahiko Tanabe, Masakazu Akahori, Toshimitsu Ichijo, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda

{"title":"Germline pathogenic variants detected by GenMineTOP: insight from a nationwide tumor/normal paired comprehensive genomic profiling test, in Japan.","authors":"Eri Habano, Miho Ogawa, Kousuke Watanabe, Nana Akiyama, Hyangri Chang, Mirei Ka, Aya Shinozaki-Ushiku, Masahiko Tanabe, Masakazu Akahori, Toshimitsu Ichijo, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda","doi":"10.1038/s10038-025-01389-z","DOIUrl":"https://doi.org/10.1038/s10038-025-01389-z","url":null,"abstract":"Comprehensive genomic profiling (CGP) expands treatment options for solid tumor patients and identifies hereditary cancers. However, in Japan, confirmatory tests have been conducted in only 31.6% of patients with presumed germline pathogenic variants (GPVs) detected through tumor-only testing. Paired tumor-normal analysis enables differentiation between somatic and germline variants. GenMineTOP, covered by Japan's national health insurance since August 2023, analyzes paired samples and reports GPVs in 40 genes. This study provides an initial characterization of GPVs based on clinical findings collected during the first year of GenMineTOP implementation. We analyzed 1356 solid tumor patients who underwent GenMineTOP testing in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between August 2023 and July 2024, focusing on GPV detection rates, gene distribution, and comparisons with other CGP tests. Among the analyzed cancer types, GenMineTOP had a higher proportion of CNS/brain, soft tissue, bone, and head and neck cancers compared to other CGP tests. GPVs were detected in 73 patients (5.4%), with 38.2% classified as off-tumor. HR-related GPVs (ATM, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D) were found in both males (median age: 69) and females (median age: 54). Among males, 57.9% were aged 65 or older. GPVs may be detected in any cancer patients, including those with off-tumor findings, particularly in older male patients, especially in HR-related genes. These findings support the use of paired CGP to improve the diagnosis of hereditary cancers that could otherwise remain undetected.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029646","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

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

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

{"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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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

Journal of Human Genetics Pub Date : 2025-09-05 DOI: 10.1038/s10038-025-01398-y

Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino

{"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":"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.","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

Journal of Human Genetics Pub Date : 2025-09-02 DOI: 10.1038/s10038-025-01396-0

Tadahisa Mikami, Shuji Mizumoto, Hiroshi Kitagawa, Shuhei Yamada

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

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

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

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

{"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":"https://doi.org/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":" ","pages":""},"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

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

{"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":"https://doi.org/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":" ","pages":""},"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

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