Journal of Human Genetics最新文献

{"title":"Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia.","authors":"Mohamed S Abdel-Hamid, Rasha M Elhossini, Sherif F Abdel-Ghafar, Mennat Mehrez, Mona S Aglan, Nehal F Hassib","doi":"10.1038/s10038-025-01328-y","DOIUrl":"10.1038/s10038-025-01328-y","url":null,"abstract":"<p><p>Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by short stature, skeletal deformities, and dentinogenesis imperfecta (DI). Although the majority of cases were associated with biallelic variants in TRIP11, one study described a homozygous truncating variant in MIA3, encoding TANGO1, in four sibs with ODCD in association with insulin-dependent diabetes, hearing loss, obesity, and intellectual disability. Subsequently, a homozygous truncating variant in the luminal domain of TANGO1 was identified in a fetus with a lethal skeletal dysplasia and fetal hydrops. Herein, we describe two unrelated patients with a distinct phenotype including severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, and DI. Other variable features were scoliosis, squint, and cardiac problems. Exome sequencing revealed two homozygous MIA3 variants in the luminal domain of TANGO1, c.354+2T>G and p.Cys38Phe. The c.354+2T>G variant was confirmed by investigating the patient's mRNA to result in exon 3 skipping and an inframe deletion of 29 amino acids. Our patients lacked the extra-skeletal manifestations noted in the four sibs with MIA3 variant. However, they had more severe skeletal deformities closely resembling those observed in patients with TRIP11 variants. Our study suggests the presence of a phenotypic spectrum associated with MIA3 variants including ODCD with milder skeletal deformities, a classic ODCD with severe skeletal deformities, and a lethal skeletal dysplasia at the severe end of the spectrum. Although the striking phenotypic variability appears to be related to the type and or the location of the MIA3 variants, the influence of other factors cannot be ruled out.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"257-263"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677012","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":"Genetic effects on gestational diabetes mellitus and their interactions with environmental factors among Japanese women.","authors":"Tomoki Kawahara, Nobutoshi Nawa, Keiko Murakami, Toshihiro Tanaka, Hisashi Ohseto, Ippei Takahashi, Akira Narita, Taku Obara, Mami Ishikuro, Masatsugu Orui, Aoi Noda, Genki Shinoda, Yuki Nagata, Satoshi Nagaie, Soichi Ogishima, Junichi Sugawara, Shigeo Kure, Kengo Kinoshita, Atsushi Hozawa, Nobuo Fuse, Gen Tamiya, Wendy L Bennett, Margaret A Taub, Pamela J Surkan, Shinichi Kuriyama, Takeo Fujiwara","doi":"10.1038/s10038-025-01330-4","DOIUrl":"10.1038/s10038-025-01330-4","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) is common in Japanese women, posing serious risks to mothers and offspring. This study investigated the influence of maternal genotypes on the risk of GDM and examined how these genotypes modify the effects of psychological and dietary factors during pregnancy. We analyzed data from 20,399 women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort. Utilizing two customized SNP arrays for the Japanese population (Affymetrix Axiom Japonica Array v2 and NEO), we performed a meta-analysis to combine the datasets. Gene-environment interactions were assessed by modeling interaction terms between genome-wide significant single nucleotide polymorphisms (SNPs) and psychological and dietary factors. Our analysis identified two SNP variants, rs7643571 (p = 9.14 × 10^-9) and rs140353742 (p = 1.24 × 10^-8), located in an intron of the MDFIC2 gene, as being associated with an increased risk of GDM. Additionally, although there were suggestive patterns for interactions between these SNPs and both dietary factors (e.g., carbohydrate and fruit intake) and psychological distress, none of the interaction terms remained significant after Bonferroni correction (p < 0.05/8). While nominal significance was observed in some models (e.g., psychological distress, p = 0.04), the data did not provide robust evidence of effect modification on GDM risk once adjusted for multiple comparisons. These findings reveal novel genetic associations with GDM in Japanese women and highlight the importance of gene-environment interactions in its etiology. Given that previous genome-wide association studies (GWAS) on GDM have primarily focused on Western populations, our study provides new insights by examining an Asian population using a population-specific array.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"265-273"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677014","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":"Functional verification and allele-specific silencing of a novel AKT3 variant that causes megalencephaly, polymicrogyria and intractable epilepsy.","authors":"Yosuke Miyamoto, Takenori Tozawa, Eisuke Ichise, Tatsuji Hasegawa, Takahiro Fujimoto, Kyoko Itoh, Masafumi Morimoto, Tomoko Iehara, Tomohiro Chiyonobu","doi":"10.1038/s10038-025-01329-x","DOIUrl":"10.1038/s10038-025-01329-x","url":null,"abstract":"<p><p>AKT3, a key component of the PI3K-AKT-MTOR pathway, is highly expressed in the brain, and its activating variants cause megalencephaly and cortical malformations. In this study, we functionally verified a novel missense AKT3 variant (p.Q78R) identified in a patient with extreme megalencephaly and intractable epilepsy. We transiently transfected HEK-293T cells with the AKT^WT or AKT3^Q78R and observed a significant increase of phospho-S6, a marker of mTOR complex 1 (mTORC1) activity, in AKT3^Q78R transfected cells. Furthermore, considering its application in epilepsy treatment research, we identified a small interfering RNA (siRNA) capable of reducing the mRNA levels of AKT^Q78R without affecting the expression levels of AKT3^WT. Finally, the siRNA we identified specifically suppressed the AKT3^Q78R-mediated mTORC1 activity, suggesting that this allele-specific siRNA approach holds promise for ameliorating the pathological condition.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"281-285"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular gene signature of circulating stromal/stem cells.","authors":"Weiping Lin, Liangliang Xu, Gang Li, Micky Daniel Tortorella","doi":"10.1038/s10038-025-01322-4","DOIUrl":"10.1038/s10038-025-01322-4","url":null,"abstract":"<p><p>The human skeleton is renewed and regenerated throughout life, by a cellular process known as bone remodeling. Stem cells are clono-genic cells that are capable of differentiation into multiple mature cell types (multipotency), and simultaneously replenishing stem cell pool (self-renewal), which allows them to sustain tissue development and maintenance. Circulating mesenchymal stromal/stem cells (MSCs), are mobile adult stem cells with specific gene expression profiling, as well as enhanced mitochondrial remodeling as a promising source for personalized cell and gene therapy. A global LGR5-associated genetic interaction network highlights the functional organization and molecular phenotype of circulating MSCs.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"275-280"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605004","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 step forward in genetic counselling: defining practice and ethics through the Genetic Counselling Practice Consortium in Hong Kong.","authors":"Desiree M S Tse, Brian H Y Chung, Annie T W Chu","doi":"10.1038/s10038-025-01321-5","DOIUrl":"10.1038/s10038-025-01321-5","url":null,"abstract":"<p><p>Genetic counselling plays a crucial role in the genomic era, assisting in disease risk determination, diagnosis and management. The lack of an accredited local training program for genetic counselling in Hong Kong has led to pragmatic on-the-job training and diverse practice models. In view of the needs for enhanced awareness in genomic counselling practices among healthcare professionals, a collaborative effort - the Hong Kong Genetic Counselling Practice Consortium - was initiated to develop genomic medicine in Hong Kong. A thematic analysis of genetic counselling practice across 15 regions was conducted, revealing a broad consistency in the scope of duties, with minor differences due to social and cultural influences. Genetic counsellors generally follow a similar protocol, but some approaches vary. Ethical considerations for genetic counsellors are discussed, highlighting their responsibility towards themselves, colleagues, clients, and society. The scope of practice and code of ethics were developed to highlight the key areas of practice duties; guide the conduct of genetic counsellors; and support local counsellors in their professional training, ultimately contributing to the advancement of genomic science and health benefit of the people of Hong Kong.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"233-241"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634126","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":"Translocation-specific polymerase chain reaction in preimplantation genetic testing for recurrent translocation carrier.","authors":"Gen Furukawa, Rie Kawamura, Hidehito Inagaki, Yoshihiko Sakakibara, Yoshimasa Asada, Tetsuaki Hara, Takeshi Iwasa, Akira Kuwahara, Minoru Irahara, Hiroki Kurahashi","doi":"10.1038/s10038-025-01327-z","DOIUrl":"10.1038/s10038-025-01327-z","url":null,"abstract":"<p><p>It is occasionally necessary to distinguish balanced reciprocal translocations from normal diploidy since balanced carriers can have reproductive problems or manifest other disease phenotypes. It is challenging to do this however using next generation sequencing (NGS) or microarray-based preimplantation genetic testing (PGT). In this study, discarded embryos were harvested from balanced reciprocal translocation carriers intending PGT that were determined to be unsuitable for transfer due to unbalanced translocations or translocation-unrelated aneuploidy. Two trophoectoderm biopsy samples were obtained from each single embryo. Whole genome amplification (WGA) was performed either by looping-based amplification (LBA) or multiple displacement amplification (MDA). NGS-based copy number variation (CNV) analysis as well as translocation-specific PCR was performed for each. We used embryo samples from t(8;22)(q24.13;q11.2) and t(11;22)(q23;q11.2) carriers since they are recurrent constitutional translocations that have nearly identical breakpoints even among independent unrelated families. CNV analysis was generally consistent between the two WGA methods. Translocation-specific PCR allowed us to detect each derivative chromosome in the MDA WGA samples but not with the LBA method, presumably due to coverage bias or the shorter sized WGA products. We successfully distinguished balanced reciprocal translocations from normal diploidy in normal samples with CNV analysis. A combination of CNV analysis and translocation-specific PCR using MDA-amplified WGA product can distinguish between balanced reciprocal translocation and normal diploidy in preimplantation genetic testing for structural rearrangements (PGT-SR).</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"249-255"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515663","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":"Beyond CHD7 gene: unveiling genetic diversity in clinically suspected CHARGE syndrome.","authors":"Dohyung Kim, Ji-Hee Yoon, Hyunwoo Bae, Soojin Hwang, Go Hun Seo, June-Young Koh, Young Seok Ju, Hyo-Sang Do, Soyoung Kim, In Hee Choi, Gu-Hwan Kim, Ja Hye Kim, Jin-Ho Choi, Beom Hee Lee","doi":"10.1038/s10038-025-01325-1","DOIUrl":"10.1038/s10038-025-01325-1","url":null,"abstract":"<p><p>The Verloes or Hale diagnostic criteria have been applied for diagnosing CHARGE syndrome in suspected patients. This study was conducted to evaluate the diagnostic rate of CHD7 according to these diagnostic criteria in suspected patients and also to investigate other genetic defects in CHD7-negative patients. The clinical findings and the results of genetic testing of CHD7, chromosome microarray, exome sequencing, or genome sequencing of 59 subjects were reviewed. CHD7 pathogenic variants were identified in 78% of 46 subjects who met either the Verloes or Hale diagnostic criteria and in 87% of 38 subjects who met both criteria, whereas no CHD7 variant was detected in 13 subjects who met neither criterion. Among 23 patients without the CHD7 variant, six genetic diseases were identified in 7 patients, including Wolf-Hirschhorn syndrome, 1q21 deletion syndrome, 19q13 microdeletion, and pathogenic variants in PLCB4, TRRAP, and OTX2. Based on these comprehensive analyses, the overall diagnostic rate was 73% for seven different genetic diseases. This study emphasizes the importance of comprehensive clinical and genetic evaluation in patients with clinically suspected CHARGE syndrome, recognizing the overlapping phenotypes in other rare genetic disorders.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"243-248"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501879","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":"Profiling of runs of homozygosity from whole-genome sequence data in Japanese biobank.","authors":"Aye Ko Ko Minn, Motomichi Matsuzaki, Akira Narita, Takamitsu Funayama, Yurii Kotsar, Satoshi Makino, Jun Takayama, Shinichi Kuriyama, Gen Tamiya","doi":"10.1038/s10038-025-01331-3","DOIUrl":"https://doi.org/10.1038/s10038-025-01331-3","url":null,"abstract":"<p><p>Runs of homozygosity (ROHs) are widely observed across the genomes of various species and have been reported to be associated with many traits and common diseases, as well as rare recessive diseases, in human populations. Although single nucleotide polymorphism (SNP) array data have been used in previous studies on ROHs, recent advances in whole-genome sequencing (WGS) technologies and the development of nationwide cohorts/biobanks are making high-density genomic data increasingly available, and it is consequently becoming more feasible to detect ROHs at higher resolution. In the study, we searched for ROHs in two high-coverage WGS datasets from 3552 Japanese individuals and 192 three-generation families (consisting of 1120 family members) in prospective genomic cohorts. The results showed that a considerable number of ROHs, especially short ones that may have remained undetected in conventionally used SNP-array data, can be detected in the WGS data. By filtering out sequencing errors and leveraging pedigree information, longer ROHs are more likely to be detected in WGS data than in SNP-array data. Additionally, we identified gene families within ROH islands that are associated with enriched pathways related to sensory perception of taste and odors, suggesting potential signatures of selection in these key genomic regions.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772418","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":"Hyaluronidase 2 deficiency due to novel compound heterozygous variants in HYAL2: a case report of siblings with HYAL2 deficiency showing different clinical severity and literature review.","authors":"Ryuta Orimoto, Eriko Adachi, Maki Gau, Yoko Saito, Haruki Yamano, Hisae Nakatani, Shizuka Kirino, Kengo Moriyama, Yohei Yamaguchi, Tomoko Mizuno, Taku Ishii, Masayuki Yoshida, Kenichi Kashimada, Kei Takasawa","doi":"10.1038/s10038-025-01333-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01333-1","url":null,"abstract":"<p><p>This study reports the first Asian case of syndromic cleft lip and palate resembling CHARGE-like syndrome, caused by novel compound heterozygous variants of the HYAL2 gene. Hyaluronidase-2 (HYAL2) plays a critical role in hyaluronic acid degradation and tissue remodelling. A 2-year-old Japanese boy presented with growth deficiency, congenital heart disease, craniofacial dysmorphism, micropenis, and developmental delays-features that overlapped with those of CHARGE syndrome. Genetic analysis identified two rare HYAL2 missense variants (c.1133G>A, p.Arg378His; c.1271A>G, p.His424Arg), classified as \"likely pathogenic\" based on ACMG/AMP criteria. This case highlights the importance of considering HYAL2 deficiency in the syndromic presentation of cleft lip and palate with congenital heart disease, particularly in the absence of CHD7 abnormalities. This study also emphasizes potential primary testicular dysfunction in male patients with HYAL2 deficiency and underscores the need for further research to clarify genotype-phenotype correlations and pathology.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753057","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 case of autosomal-dominant cutis laxa caused by a de novo likely pathogenic variant in ALDH18A1: case report and literature review.","authors":"Firoz Ahmad, Pradnya Gadgil, Noopur Navandar, Sapna Sandal, Mukesh Kumar, Amisha Shah, Meenu Angi, Pooja Chaudhary, Ekta Jajodia, Toral Vaishnani, Anindyajit Banerjee, Spandan Chaudhary, Neeraj Arora","doi":"10.1038/s10038-025-01334-0","DOIUrl":"https://doi.org/10.1038/s10038-025-01334-0","url":null,"abstract":"<p><p>Cutis laxa is a highly heterogeneous connective tissue disorder characterized by progressively loose skin, often accompanied by systemic involvement. Autosomal dominant cutis laxa (ADCL) has been linked to variants in several genes, including ALDH18A1, which encodes Δ1-pyrroline-5-carboxylate synthetase, a key enzyme in proline and collagen metabolism. We report a novel case of ADCL in a 1.6-year-old patient presenting with growth delay, hypotonia, joint laxity, lax skin, cataract, dysmorphic features, microcephaly, cranial vessel tortuosity, hip dislocation, and psychomotor retardation. Whole-exome sequencing revealed a de novo heterozygous c.400 T > C (p.Ser134Pro) substitution in the ALDH18A1 gene. This variant has not been previously reported, and it is the first report of an individual with ALDH18A1-ADCL due to a substitution at a highly conserved residue, p.Ser134 of the P5CS protein. Our findings expand the mutational spectrum of ALDH18A1-related ADCL and highlight the importance of genetic testing in diagnosing rare disorders.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753055","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}