Journal of Human Genetics最新文献

{"title":"A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.","authors":"Qianyun Cai, Haijiao Wang, Rong Luo, Xiao Qian, Zhongjie Zhou","doi":"10.1038/s10038-025-01411-4","DOIUrl":"https://doi.org/10.1038/s10038-025-01411-4","url":null,"abstract":"<p><p>Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225374","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":"Perinatal outcomes of fetal CNVs detected by genome-wide non-invasive prenatal testing in Japan.","authors":"Yuka Yamashita, Nahoko Shirato, Tatsuko Ishii, Mikiko Izumi, Kiyotake Ichizuka, Makiko Tominaga, Reina Komatsu, Tetsuro Kondo, Seiji Wada, Haruhiko Sago, Yuki Ito, Osamu Samura, Nobuhiro Suzumori, Hideaki Sawai, Yukiko Katagiri, Yoshiki Maeda, Hiroko Morisaki, Akira Namba, Yoshimasa Kamei, Junko Yotsumoto, Yuri Hasegawa, Kiyonori Miura, Setsuko Nakayama, Satoshi Kawaguchi, Haruka Hamanoue, Kazuya Mimura, Yuko Matsubara, Yoko Okamoto, Arisa Fujiwara, Kazutoshi Maeda, Takafumi Watanabe, Akinori Ida, Hiromi Hayakawa, Koshichi Goto, Akihiko Sekizawa","doi":"10.1038/s10038-025-01409-y","DOIUrl":"https://doi.org/10.1038/s10038-025-01409-y","url":null,"abstract":"<p><p>Non-invasive prenatal testing (NIPT) enables the screening of fetal chromosomal abnormalities by analyzing cell-free DNA (cfDNA) in maternal blood. Recent technological advancements have expanded its applications to the detection of copy number variations (CNVs). However, the clinical utility of CNV detection remains unclear. We aimed to investigate the association between fetal CNVs detected by genome-wide NIPT and perinatal outcomes in a large cohort in Japan. This retrospective cohort study included 46,082 patients who underwent NIPT at certified facilities in Japan between January 2015 and September 2021. Genome-wide NIPT was performed using massively parallel sequencing to detect fetal CNVs exceeding 7 Mb. Despite their small size, well-characterized microdeletions, such as 22q11.2 were included. From 46,082 patients with NIPT results, 30,373 cases with known birth outcomes were extracted, and cases with fetal CNV were included in the analysis. Fetal CNVs were detected in 66 patients (0.2%). Adverse outcomes, including miscarriage, growth restriction, and structural abnormalities, were observed in 14 of the 66 cases (21.2%). Pathogenic CNVs were frequently detected even in the 52 cases (78.8%) with favorable outcomes. Genome-wide NIPT may assist in the diagnosis of cases with structural abnormalities when combined with confirmatory testing. Our findings demonstrate that pathogenic CNVs are also detected in a substantial number of structurally normal fetuses with favorable short-term outcomes. This discordance presents a significant challenge for prenatal counseling. The clinical significance of the findings should be clarified through confirmatory testing of CNV cases and the accumulation of data from long-term follow-up studies.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149599","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":"Biosynthesis of GPI anchored proteins, its deficiencies and treatment.","authors":"Yoshiko Murakami","doi":"10.1038/s10038-025-01379-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01379-1","url":null,"abstract":"<p><p>Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149631","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":"Balanced chromosomal insertions as the mechanism of recurrent familial microstructural abnormalities: detailed analyses using long-read whole-genome sequencing.","authors":"Hironao Shirai, Keiko Shimojima Yamamoto, Hirokazu Arai, Yukio Sawaishi, Saori Fujita, Yoko Kuriyama, Masaki Miura, Jun Tohyama, Toshiyuki Yamamoto","doi":"10.1038/s10038-025-01408-z","DOIUrl":"https://doi.org/10.1038/s10038-025-01408-z","url":null,"abstract":"<p><p>Chromosomal insertions are a type of structural abnormality. While individuals with balanced insertions are typically asymptomatic, their offspring may have unbalanced abnormalities. We report two families with recurrent microstructural chromosomal abnormalities. To investigate the mechanisms, we performed chromosomal microarray (CMA), fluorescence in situ hybridization (FISH), and long-read whole-genome sequencing. In Family A, a duplication of 13q31.2-q33.1 was found in a proband with developmental and epileptic encephalopathy. A reciprocal deletion was detected in a fetus during a subsequent pregnancy. FISH confirmed an interchromosomal insertion involving chromosome 10. Long-read sequencing in the carrier parent revealed two split fragments of the inserted segment, one in inverted orientation. In Family B, a recurrent 1p36 interstitial deletion was associated with intellectual disability. FISH showed no abnormalities in the parents, but long-read sequencing of a suspected carrier revealed an intrachromosomal insertion of the 1p36 segment in inverted orientation. Breakpoint analysis showed minimal deletions or fragment overlaps in both families, indicating chromoanasynthesis as the likely mechanism. Although not routinely required for diagnosis of insertions, long-read sequencing can reveal hidden structural changes and clarify insertion mechanisms, as demonstrated in this study.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137877","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":"LEO1 haploinsufficiency is associated with developmental delays and autism spectrum disorder.","authors":"Emilie C Ung, Nicholas A Borja","doi":"10.1038/s10038-025-01410-5","DOIUrl":"https://doi.org/10.1038/s10038-025-01410-5","url":null,"abstract":"<p><p>LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare LEO1 variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in LEO1 c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports LEO1 haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137868","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":"Evidence of maternal inheritance of Nizon-Isidor syndrome in an individual with GAMT and TNFRSF13B sequence variants.","authors":"Dibyendu Dutta, Jennifer Black, Daniela Macaya, Bobbi McGivern, Ria Garg","doi":"10.1038/s10038-025-01407-0","DOIUrl":"https://doi.org/10.1038/s10038-025-01407-0","url":null,"abstract":"<p><p>Nizon-Isidor syndrome (NIZIDS) is a rare neurodevelopmental disorder caused by heterozygous MED12L variants, where previously pathogenic single-nucleotide variants (SNVs) were only reported as de novo events. Here, we report the first case of maternally inherited MED12L nonsense variant in NIZIDS. Clinical assessment and family history evaluation revealed global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment. Exome sequencing (ES) of the proband and both parents confirmed the presence of a maternally inherited likely pathogenic MED12L nonsense variant in the proband. Additional pathogenic variants in GAMT (maternal) and TNFRSF13B (paternal) genes were also identified in the proband. The clinical history of the mother suggested variable expressivity of the MED12L variant. Our case report challenges the presumed de novo inheritance of MED12L SNVs and demonstrates variable expressivity, thereby highlighting the benefit of a complete phenotype-driven approach when analyzing exome and genome data.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075459","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":"Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome.","authors":"Sachiko Nishina, Kaoruko Torii, Shizuka Ishitani, Tomoyo Yoshida, Maki Fukami, Kenji Kurosawa, Kenjiro Kosaki, Hirotomo Saitsu, Tohru Ishitani, Yoshihiro Hotta","doi":"10.1038/s10038-025-01395-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01395-1","url":null,"abstract":"<p><p>Cyclin-dependent kinase 9 (CDK9) phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) to regulate transcription. Previously, we reported that an 8-year-old boy with the biallelic CDK9 variants p.A288T and p.R303C exhibited a CHARGE-like malformation syndrome in which retinal dystrophy was a distinguishing feature. This dystrophy was caused by the decreased CDK9 kinase activity associated with these variant alleles [wild-type (WT) > A288T > R303C]. In this study, we describe a female patient who also bears biallelic CDK9 variants but displays retinal dystrophy without a CHARGE-like malformation syndrome. Trio-based whole-exome sequencing identified a new variant CDK9 allele, p.P321S, that occurred de novo in the patient. As a result, this female patient displayed compound heterozygous variants composed of the p.A288T CDK9 variant of maternal origin plus the novel p.P321S variant. With respect to reduced kinase activity, the new variant could be ranked as WT > P321S > A288T. Thus, our study raises a possibility that retinal dystrophy can arise with or without a CHARGE-like malformation syndrome depending on the level of kinase activity associated with the combination of variant CDK9 alleles present.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069709","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":"The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia.","authors":"Vera G Pshennikova, Fedor M Teryutin, Tuyara V Borisova, Georgii P Romanov, Alexandra M Cherdonova, Alena A Nikanorova, Igor V Morozov, Alexander A Bondar, Aisen V Solovyev, Sardana A Fedorova, Nikolay A Barashkov","doi":"10.1038/s10038-025-01406-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01406-1","url":null,"abstract":"<p><p>Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene. In this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia). Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound). Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies. In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age. In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA_{0.5,1.0,2.0,4.0 kHz}) per year until reaching profound deafness in the second or third decade of the life. The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians). The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes. We conclude that the high prevalence of DFNB103 in Eastern Siberia is the result of founder effect, which occurred ~2500 years ago (~78 generations). These findings expand our knowledge of causative role of pathogenic variants in CLIC5 gene to the etiology of the HL.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075446","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":"Meiotic determinants of unbalanced gametogenesis in chromosomal inversion carriers.","authors":"Shuo Zhang, Yaqiong He, Yao Lu, Yi Huang, Jiaan Huang, Yichao Niu, Yueping Zhang, Yanzhi Du, Yun Sun, Ting Zhang, Zhe Wei","doi":"10.1038/s10038-025-01402-5","DOIUrl":"https://doi.org/10.1038/s10038-025-01402-5","url":null,"abstract":"<p><p>Preimplantation genetic testing for structural rearrangements (PGT-SR) has already been applied in inversion carriers. However, it has not been well clarified which inversion carriers should be recommended for PGT-SR in clinical practice. In this study, we retrospectively analyzed the segregation patterns of inverted loops in 522 blastocysts derived from 145 PGT-SR cycles. Multivariate logistic regression models were applied to identify independent predictors of unbalanced gamete production, while correlation analysis assessed the relationship between the rate of unbalanced embryos and inverted segment length. Among all embryos analyzed, 73 unbalanced embryos (13.98%, 73/522) related to the chromosome inversions originating from 33 carriers (31.43%, 33/105) were identified. Multivariate logistic regression showed neither the carrier's gender nor age affected the production of unbalanced embryos. In contrast, the probability in the pericentric inversion group was significantly higher than that in the paracentric inversion group (p < 0.001), and significant difference was also identified among different chromosomal groups, with groups A (Chr1-3) and C (Chr 6-12) showing higher rates than other groups (p = 0.034). Moreover, we found the haploid autosomal length (HAL) and the ratio of inverted segment size in carriers who produced unbalanced embryos were significantly higher than in those who did not (p < 0.001). Furthermore, our results indicated a positive correlation between Segment size% and the rate of unbalanced embryos (p = 0.042, r = 0.357). In conclusion, carriers of pericentric inversions involving chromosomes from groups A and C are more prone to producing unbalanced embryos. Furthermore, a larger inverted segment size is associated with a higher frequency of unbalanced embryos.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075431","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":"Diversity challenges and reconciles genetics in facioscapulohumeral muscular dystrophy.","authors":"Mitsuru Sasaki-Honda, Takumi Kishimoto, Hidetoshi Sakurai","doi":"10.1038/s10038-025-01401-6","DOIUrl":"https://doi.org/10.1038/s10038-025-01401-6","url":null,"abstract":"<p><p>Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease with an estimated prevalence of no more than 1 in 8000; however, it is among the most common myopathies affecting global populations. This condition is classically categorised into two genetic types, FSHD1 (MIM: 158900) and FSHD2 (MIM: 158901), which, although have different genetic causes, are phenotypically indistinguishable, manifesting as progressive muscle weakness primarily affecting the face and periscapular muscles, as well as other muscle groups in later stages. The intense efforts of clinical and basic studies to understand this disease have revealed the critical necessity for disease manifestation: ectopic activation of the embryogenic and germline gene DUX4 (double homeobox 4, MIM: 606009) in skeletal muscles and the genetic and epigenetic backgrounds allowing DUX4 expression. Thus, the potential target therapies of FSHD include silencing DUX4 transcription or blocking its translation. Although the central role of DUX4 in FSHD pathology has almost reached a consensus, the mechanism of its activation remains largely unclear. Notably, the clinical dissection of genotype-epigenotype-phenotype observations, including non-penetrant and asymptomatic carriers of permissive genetic backgrounds, highlights the yet unsolved clinical diversity with potential additional layers of DUX4 regulation or other disease-modifying factors. This review provides an overview of essential findings with potential implications for further understanding the mechanisms underlying diverse clinical cases of FSHD and endogenous DUX4 activation in FSHD pathology.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075395","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}