Journal of Human Genetics最新文献

{"title":"Rare variants in embryonic development and cell signalling genes in syndromic and non-syndromic orofacial clefts: evidence from a Colombian Caribbean cohort","authors":"Alejandro Silva, Carolina Jaramillo Oquendo, Jaime E. Bernal, Julio Cesar Martinez, Andrew Collins, Ignacio Briceño, Escilda Benavides, Zulieth López Arrieta, Sarah Ennis","doi":"10.1038/s10038-026-01466-x","DOIUrl":"10.1038/s10038-026-01466-x","url":null,"abstract":"Orofacial clefts (OFCs) are common craniofacial malformations broadly classified as syndromic or non-syndromic. While syndromic OFCs are often caused by rare, high-impact variants, non-syndromic OFCs are typically associated with multiple low-impact common variants. However, growing evidence suggests that rare variants may also contribute to non-syndromic OFCs. To explore this, we performed exome sequencing in 45 individuals from 20 Colombian families, predominantly from the Caribbean region, a genetically distinct and underrepresented population. Our goal was to identify rare variants potentially contributing to both syndromic and non-syndromic OFCs. We identified 15 rare protein-altering variants in 11 families that showed strong phenotype-genotype concordance. Four probands carried a previously reported common ACSS2 variant (c.1487 T > C), with two probands also harbouring variants in Pleckstrin Homology Domain Containing (PLEKH) genes. Five variants were previously reported in ClinVar (two with conflicting interpretations, one pathogenic, and two of uncertain significance), while ten were novel. Variants were found in known OFC-associated genes (MID1, FLNA, FGF10) and emerging candidates (ZFHX4, PLEKHA5, PLEKHA7). These findings provide further evidence that rare variants in developmental and signalling pathways contribute to both syndromic and non-syndromic OFCs, reinforcing previous studies and expanding the catalogue of candidate genes in underrepresented populations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"443-451"},"PeriodicalIF":2.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-026-01466-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581452","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":"Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat expansions","authors":"Hiraku Matsuura, Daiki Fukunaga, Ikuko Mizuta, Chisato Tamai, Rei Yasuda, Mao Mukai, Akiko Watanabe-Hosomi, Takashi Koizumi, Tomokatsu Yoshida, Tomoyuki Ohara, Takashi Kasai, Jun Sone, Toshiki Mizuno","doi":"10.1038/s10038-026-01470-1","DOIUrl":"10.1038/s10038-026-01470-1","url":null,"abstract":"Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant inherited neurodegenerative disease caused by NOTCH2NLC GGC repeat expansions. A high-intensity signal in the corticomedullary junction (CMJ) on magnetic resonance (MR) diffusion-weighted imaging (DWI) is a well-known characteristic of NIID. However, because of its diverse clinical symptoms and frequent presence of cerebral white matter hyperintensity (WMH) lesions on MRI, patients with NIID may be suspected of having other leukoencephalopathies. The aim of the present study was to identify patients with NOTCH2NLC GGC repeat expansions among those with undiagnosed leukoencephalopathies, recruited from NOTCH3-negative cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-suspected and GFAP-negative Alexander disease (AxD)-suspected patients. Among 459 NOTCH3-negative CADASIL-suspected patients, 18 (3.9%) showed NOTCH2NLC GGC repeat expansions; however, among 40 GFAP-negative AxD-suspected patients, none exhibited such repeat expansions. On comparing 17 patients with GGC repeat expansions, whose clinical information was available, with 179 CADASIL probands previously reported by us, the former showed significantly higher frequencies of seizure (23.5 vs. 6.9%, respectively), WMH in the corpus callosum (92.9 vs. 9.2%, respectively), paravermis (21.4 vs. 2.7%, respectively), and middle cerebellar peduncle (21.4 vs. 3.4%, respectively), and DWI high-intensity signals in CMJ (61.5 vs. 1.4%, respectively). In conclusion, not only DWI high-intensity signals in CMJ, but also the WMH distribution, particularly a high frequency in the corpus callosum, and presence of seizures are useful for detecting NIID in patients with undiagnosed leukoencephalopathies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 8","pages":"479-484"},"PeriodicalIF":2.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512599","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 compound heterozygous YY1AP1 variant in Grange syndrome: importance of early signs in preventing life-threatening vascular complications","authors":"Gul Unsel-Bolat, Neslihan Tezcan, Dilan Genç-Akdağ, Hamide Betül Gerik-Celebi, Alperen Tezcan, Hilmi Bolat","doi":"10.1038/s10038-026-01471-0","DOIUrl":"10.1038/s10038-026-01471-0","url":null,"abstract":"Grange syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in the YY1AP1 gene. It is clinically characterized by multisystem involvement, including vascular stenosis, brachysyndactyly, osteopenia, cardiac anomalies, and neurodevelopmental delay. Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Whole-exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis. We report a 17-year-old Turkish female who presented with academic failure, speech delay, dysarthria, facial dysmorphism, and surgically corrected hand syndactyly. Notably, she exhibited no clinical signs of vascular stenosis or hypertension at the time of diagnosis. A novel compound heterozygous variant combination in YY1AP1 (NM_139119.3) was identified: c.1489_1492del (p.Glu636ProfsTer13), previously reported as pathogenic, and c.1637_1638del (p.Pro546ArgfsTer26), a novel frameshift variant. These variants were maternally and paternally inherited, respectively. This is the first reported case of Grange syndrome diagnosed based on neurodevelopmental and dysmorphic findings before the onset of vascular or hypertensive symptoms. Our findings highlight the importance of considering YY1AP1-related pathology in the differential diagnosis of intellectual disability and syndactyly, even in the absence of vascular features. Early genetic diagnosis enables clinical surveillance for life-threatening complications associated with this syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 8","pages":"485-492"},"PeriodicalIF":2.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13400299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512612","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":"Genetic diagnosis of sibling cases initiated by identification of outlier gene expression using transcriptome analysis of urine-derived cells","authors":"Toru Takagi, Sachiko Miyamoto, Kenji Shimizu, Yasuhiko Tanaka, Tomoko Matsubayashi, Yohei Masunaga, Hirotomo Saitsu","doi":"10.1038/s10038-026-01472-z","DOIUrl":"10.1038/s10038-026-01472-z","url":null,"abstract":"Transcriptome analysis can improve the diagnostic yield for neurodevelopmental disorders. We applied RNA-seq using urine-derived cells (UDCs) to a family with two affected brothers with a muscular dystrophy–dystroglycanopathy and dilated cardiomyopathy. Exome sequencing identified a maternally inherited heterozygous B3GALNT2 splice-site variant (NM_152490.5:c.261-2A>G) but no second pathogenic allele. UDCs RNA-seq with OUTRIDER detected markedly decreased expression of B3GALNT2 in the proband and a milder decrease in the father, suggesting a paternally inherited non-coding variant. Genome sequencing revealed a 357-bp heterozygous deletion encompassing the B3GALNT2 promoter and transcription start site, which segregated with the phenotype. RNA-seq supported aberrant splicing from the splice-site allele and reduction of transcripts from the deletion allele. These findings provide proof of concept that UDCs RNA-seq–guided outlier-expression analysis can identify non-coding second hits and support genetic diagnosis, and they suggest that cardiac surveillance may be warranted in B3GALNT2-related disorder as they age.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 8","pages":"531-534"},"PeriodicalIF":2.3,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512586","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":"Interaction between human oxoguanine glycosylase 1 gene polymorphisms and smoking status on nasopharyngeal carcinoma risk","authors":"Fanyu Peng, Ruru Zhang, Rong Yu, Jing Wu, Lijun Wang, Yatian Liu, Delin Liu, Pengwei Yan, Baixia Yang","doi":"10.1038/s10038-026-01468-9","DOIUrl":"10.1038/s10038-026-01468-9","url":null,"abstract":"This study aims to evaluate the impact of four SNPs of human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene, and its interaction with smoking and alcohol drinking on the risk of nasopharyngeal carcinoma (NPC). Hardy–Weinberg equilibrium (HWE) and the relationship between four SNPs of the hOGG1 gene and the risk of NPC were tested using the SNPStats online software ( https://www.snpstats.net/start.htm ). Generalized multifactor dimensionality reduction (GMDR) was utilized to screen the optimal interaction combinations among four hOGG1 gene SNPs, smoking, and alcohol drinking. We found that rs1052133- Cys allele was associated with increased NPC risk, ORs (95% CI) were 1.42 (1.12–1.85) for Ser/Cys genotype, 1.95 (1.51–2.48) for Cys/Cys genotype, 1.57 (1.18–2.05) for Ser/Cys or Cys/Cys genotype, compared to Ser/Ser genotype. We also found that rs159153- T allele was associated with increased NPC risk, ORs (95% CI) were 1.35 (1.06–1.73) for CT genotype, 2.18 (1.62–2.85) for TT genotype, 1.45 (1.09–1.90) for CT or TT genotype, compared to CC genotype. However, we did not find any statistically significant impact of the minor alleles of rs3219008 and rs293795 on the risk of NPC. GMDR model found a significant gene-environment interaction combination (two-locus model with P = 0.018) between rs1052133 and smoking. Compared to never smokers with rs1052133 Ser/Ser genotype, ever or currently smokers with rs1052133- Ser/Cys or Cys/Cys genotype have the highest NPC risk, OR (95% CI) = 3.18 (1.94–4.42). The rs1052133 and rs159153 minor alleles, the interaction between rs1052133 and smoking, were all associated with increased NPC risk.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"461-466"},"PeriodicalIF":2.3,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503990","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":"Allelic variation in the ATP7B gene promoter. Implications for phenotype variability, neurodegeneration and Pt resistance in tumor diseases","authors":"Simona Incollu, Isadora Asunis, Stefania Satta, Salvatore Savasta, Georgios Loudianos","doi":"10.1038/s10038-026-01469-8","DOIUrl":"10.1038/s10038-026-01469-8","url":null,"abstract":"Wilson's disease (WD) is a rare genetic disorder of copper transport due to mutations in the ATP7B gene. This results in copper overload and tissue damage that is most evident in the liver and brain. Over 1000 pathogenic mutations have been found in WD patients, and of these, mutations within the ATP7B coding region predominate. In this study, we perform functional analyses of 7 rare sequence variations in the promoter region of the ATP7B gene. We performed dual luciferase reporter assays in HepG2 and SH-SY5Y cell lines under basal conditions and after the addition of 10 μM or 40 μM concentrations of CuSO4. The results showed that promoter activity varied both according to the haplotype and the cell line used. Our results suggest a potential role of promoter polymorphisms in the variation of ATP7B gene expression with probable implications in copper accumulation in the organism and consequent phenotype variation in WD. In addition, given the association of copper concentration and ATP7B expression in the brain, promoter polymorphisms could act as susceptibility determinants of neurodegeneration in the most common late-onset nervous system diseases. Finally, promoter involvement in ATP7B overexpression and platinum resistance presents new mechanisms of great importance that need to be better understood. Further experimental and clinical studies are necessary to further explore the role of the ATP7B promoter in copper and platinum management. These studies will offer new insights for the development of molecular therapies for brain degenerative and tumor diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"467-474"},"PeriodicalIF":2.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473700","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":"Expanding the phenotypic spectrum of LAMA2-related disorders: Axonal neuropathy in the absence of muscular dystrophy","authors":"Mahsa Mohammadi, Mahdieh Rahimoghli, Aida Ghasemi, Ali Asghar Okhovat, Afagh Alavi","doi":"10.1038/s10038-026-01467-w","DOIUrl":"10.1038/s10038-026-01467-w","url":null,"abstract":"The LAMA2 gene encodes the alpha-2 chain of laminin-2, a key component of the basement membrane that maintains muscle fiber stability and integrity. Mutations in this gene are linked with LAMA2-related muscular dystrophies, which includes congenital muscular dystrophy type 1 A (MDC1A) and limb-girdle muscular dystrophy autosomal recessive 23 (LGMDR23). Here, we present two siblings from one of 200 unrelated Iranian Charcot–Marie–Tooth (CMT) families, exhibiting axonal sensorimotor polyneuropathy, without any clinical signs of muscular dystrophy, carrying a homozygous variant in the LAMA2 gene. Following clinical and paraclinical assessments of the patients, genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) was employed to identify potential genetic variants, and Sanger sequencing was subsequently used to confirm the detected variant. In silico prediction tools were further applied to evaluate the potential pathogenicity and functional impact of the identified variant. A homozygous missense variant in the LAMA2 gene, c.2916 T > G; p.Phe972Leu, was identified and co-segregated with the disease status within the family, whose neurological assessments confirmed axonal sensorimotor polyneuropathy. So far, only two studies have reported LAMA2 variants in patients only manifesting a neuropathy phenotype. None of these studies reported the detailed clinical data of their cases. However, our study provides further evidence of the association between LAMA2 mutations and neuropathy, and includes comprehensive clinical and paraclinical characterization of the affected individuals. Our findings underscore the importance of comprehensive genomic testing in diagnosing neuromuscular disorders and expand the phenotypic spectrum associated with LAMA2 mutations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"453-459"},"PeriodicalIF":2.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326249","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":"Two-decade trends in prenatal genetic testing in Japan","authors":"Aiko Sasaki, Takahiro Yamada, Haruhiko Sago, Nahoko Shirato, Akihiko Sekizawa, Kenichiro Hata, Hideaki Masuzaki, Yuko Masuzawa, Toshiyuki Yamamoto, Hiroshi Yoshihashi, Shiro Tanaka, Yuka Shibata, Kanako Koike Fukushima, Kenjiro Kosaki, Shigehito Yamada, Masakazu Nishigaki, Ikuo Konishi, Hidehiko Miyake","doi":"10.1038/s10038-026-01465-y","DOIUrl":"10.1038/s10038-026-01465-y","url":null,"abstract":"Prenatal genetic testing in Japan has undergone major changes over the past 2 decades. Maternal serum screening (MSS), amniocentesis (AC), and chorionic villus sampling (CVS) have been the principal tools used to identify fetal chromosomal abnormalities. Recently, non-invasive prenatal testing (NIPT) has reshaped clinical decision-making. However, updated national-level data capturing trends in conventional prenatal testing methods are limited. We aimed to assess the current landscape of prenatal genetic testing in Japan. To update the national data, we compiled test volumes from five major high-volume laboratories that analysed prenatal genetic tests and conducted a supplemental nationwide questionnaire-based survey on ultrasound (US)-only screening between 2020 and 2023. Over this period, MSS declined from 34,887 cases in 2018 to 25,553 in 2023, AC from 16,454 in 2014 to 5620 in 2023, and CVS from 2149 in 2015 to 1167 in 2023, whereas US-only screening increased slightly to >10,000 cases annually. The chromosomal abnormality detection rate among AC cases increased from 8% during 2006–2014 to 20.0% in 2023, with trisomy 21 comprising 43.6% of the cases. During the same period, the proportion of mothers aged ≥35 years increased from 14.0% in 2003 to 30.4% in 2023, whereas the proportion of national live births decreased by 35.3%. Thus, declining test volumes cannot be attributed solely to demographic changes but also reflect the influence of NIPT uptake, improved pretest risk stratification, and changing reproductive decision-making supported by expanding genetic counselling. This study provides foundational data for future prenatal genetic testing practices and policies in Japan.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 8","pages":"475-478"},"PeriodicalIF":2.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326236","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":"Psychological distress and cancer worry in unaffected relatives undergoing cascade testing with multigene panel testing","authors":"Kaori Kimura, Takeshi Kuwata, Yumie Hiraoka, Manami Matsukawa, Chikako Tomozawa, Miki Aitani, Yu Komura, Izumi Miki, Masashi Wakabayashi, Yosuke Furui, Hiroki Kondo, Kazumasa Saigoh, Yasuko Yamamoto, Kiwamu Akagi, Hiroto Narimatsu, Megumu Yokono, Shinsuke Amano, Kaori Muto, Fuji Nagami, Kazuto Kato, Riu Yamashita, Issei Imoto, Shinji Kosugi, Makoto Hirata, Takayuki Yoshino, Yoshiaki Nakamura","doi":"10.1038/s10038-026-01464-z","DOIUrl":"10.1038/s10038-026-01464-z","url":null,"abstract":"Multigene panel testing (MGPT) is increasingly used for diagnosing hereditary cancers; however, its application in cascade testing remains limited, and the psychological impact on unaffected relatives is not well understood. This multicenter study in Japan recruited 123 first-degree relatives without a personal history of cancer to evaluate psychological responses before (T0) and two weeks after (T1) MGPT result disclosure. Participants completed the Japanese version of the Cancer Worry Scale (CWS-J) at both time points and the Impact of Event Scale–Revised (IES-R) at T1. Two weeks after disclosure, 6.5% of relatives met the threshold for clinically significant distress. Mean IES-R scores were higher among carriers of pathogenic variants (mean 8.2) than among those with negative results (mean 4.8) or variants of uncertain significance (mean 2.4). In contrast, multivariate analysis revealed no independent association between test result and post-disclosure distress. In contrast, higher baseline CWS-J scores were strongly associated with elevated IES-R scores after disclosure (p < 0.001). Children and relatives who frequently discussed cancer risk within their families exhibited higher distress levels than other subgroups. Overall, CWS-J scores showed no significant change from pre- to post-disclosure, with 41% of relatives maintaining persistently high worry. Across both time points, unaffected relatives consistently reported lower CWS-J scores than individuals with cancer (p < 0.0001). These findings suggest that MGPT has minimal psychological impact on unaffected relatives undergoing cascade testing, although those with higher preexisting cancer worry may require additional psychosocial support.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 7","pages":"435-442"},"PeriodicalIF":2.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-026-01464-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326260","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":"Glycan-related genes and genetic disorders.","authors":"Akira Togayachi, Kiyohiko Angata, Shoko Nishihara","doi":"10.1038/s10038-026-01463-0","DOIUrl":"10.1038/s10038-026-01463-0","url":null,"abstract":"<p><p>Glycosylation is a ubiquitous and essential post-translational modification in biological systems. Most cell-surface and secreted proteins are glycosylated: the glycans contribute to the structural integrity of proteins and cell membranes, and are involved in numerous physiological functions from cell-cell communication and modulation of extracellular signals to immune response and tissue development. The vast array of N-linked, O-linked, and proteoglycan-type glycans are synthesized in a stepwise manner through the coordinated action of numerous glycosyltransferases and glycosidases encoded by \"glycogenes\". At present, more than 400 glycogenes are involved in glycan biosynthesis in humans. Given the essential roles of glycosylation, it is not surprising that mutations in glycogenes cause various genetic disorders, collectively referred to as congenital disorders of glycosylation (CDGs). However, directly linking specific gene mutations to altered glycan structures and resulting clinical symptoms remains a significant challenge because the biological functions are mediated not by the enzymes themselves, but by the diverse glycan structures that they generate. Many undiagnosed rare diseases are suspected to result from defects in genes involved in glycosylation pathways. Furthermore, reports of newly identified types of CDGs are steadily increasing. Comprehensive understanding of these disorders requires a multidisciplinary approach integrating genetics, biochemistry, glycomics, and clinical research. In this review, we first describe glycans, including the different types and their biological functions. Next, all of the glycogenes involved in various synthetic pathways are presented, followed by examples of genetic disorders caused by their mutation and the glycogenomic approaches used to explore them.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147307002","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}