Journal of Human Genetics最新文献

{"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":"10.1038/s10038-025-01334-0","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"325-329"},"PeriodicalIF":2.5,"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}

{"title":"Significance of noninvasive prenatal testing using massively parallel sequencing in women with twin or vanishing twin pregnancies","authors":"Eri Takeda, Nobuhiro Suzumori, Osamu Samura, Kiyonori Miura, Yoshimasa Kamei, Hideaki Sawai, Takahiro Yamada, Kiyotake Ichizuka, Reina Komatsu, Seiji Wada, Yukiko Katagiri, Hiroko Morisaki, Setsuko Nakayama, Haruka Hamanoue, Jun Murotsuki, Kazuya Mimura, Yuko Matsubara, Kazuhisa Maeda, Akinori Ida, Mika Ito, Hiromi Hayakawa, Arisa Fujiwara, Nahoko Shirato, Tatsuko Ishii, Haruhiko Sago, Akihiko Sekizawa","doi":"10.1038/s10038-025-01332-2","DOIUrl":"10.1038/s10038-025-01332-2","url":null,"abstract":"Noninvasive prenatal testing diagnoses fetal aneuploidies in singleton pregnancies with trisomy 21, 18, or 13 accurately. However, clinical data on noninvasive prenatal testing in women with twin or vanishing twin pregnancies are limited. We report on the accuracy and prenatal and neonatal outcomes of noninvasive prenatal testing in twin and vanishing twin pregnancies. This retrospective study was conducted at 22 facilities belonging to the Noninvasive Prenatal Testing Consortium, part of a nationwide project in Japan, visited by women with twin or vanishing twin pregnancies between January 2015 and March 2022. This study investigated the accuracy and perinatal and neonatal outcomes of noninvasive prenatal testing using massively parallel sequencing in twin or vanishing twin pregnancies. Of 1013 women with twin pregnancies, 986 (97.3%) had negative; 13 (1.3%), positive; and 14 (1.4%), non-reportable noninvasive prenatal testing results. Of 225 women with vanishing twins, 203 (90.2%) had negative; 11 (4.9%), positive; and 11 (4.9%), non-reportable results. Among 1693 fetuses (77.3%) excluding 497 unknowns were available for follow-up, 1476 were from twin pregnancies, and 134 were from vanishing twin pregnancies, totaling 1610 babies has born. No false negatives were observed in the cases followed. These results indicate that noninvasive prenatal testing is useful for vanishing twin pregnancies and provide reassurance for pregnant women with twins and vanishing twins.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"297-305"},"PeriodicalIF":2.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742883","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":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"265-273"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","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":"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":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"257-263"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964919/pdf/","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":"OA","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, Hong Kong Genetic Counselling Practice Consortium, Hong Kong Genome Project, Annie T. W. Chu","doi":"10.1038/s10038-025-01321-5","DOIUrl":"10.1038/s10038-025-01321-5","url":null,"abstract":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"233-241"},"PeriodicalIF":2.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964909/pdf/","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":"OA","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":"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.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"275-280"},"PeriodicalIF":2.5,"publicationDate":"2025-03-12","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":"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":"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 AKTWT or AKT3Q78R and observed a significant increase of phospho-S6, a marker of mTOR complex 1 (mTORC1) activity, in AKT3Q78R transfected cells. Furthermore, considering its application in epilepsy treatment research, we identified a small interfering RNA (siRNA) capable of reducing the mRNA levels of AKTQ78R without affecting the expression levels of AKT3WT. Finally, the siRNA we identified specifically suppressed the AKT3Q78R-mediated mTORC1 activity, suggesting that this allele-specific siRNA approach holds promise for ameliorating the pathological condition.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"281-285"},"PeriodicalIF":2.5,"publicationDate":"2025-03-08","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":"Acknowledgment to the reviewers in 2024","authors":"Toshihiro Tanaka","doi":"10.1038/s10038-025-01324-2","DOIUrl":"10.1038/s10038-025-01324-2","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"231-232"},"PeriodicalIF":2.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-025-01324-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145122705","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":"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":"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).","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"249-255"},"PeriodicalIF":2.5,"publicationDate":"2025-02-27","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":"Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review","authors":"Jessie Poquérusse, Whitney Whitford, Juliet Taylor, Nerine Gregersen, Donald R. Love, Bobby Tsang, Kylie M. Drake, Russell G. Snell, Klaus Lehnert, Jessie C. Jacobsen","doi":"10.1038/s10038-025-01323-3","DOIUrl":"10.1038/s10038-025-01323-3","url":null,"abstract":"Autosomal dominant variants in transcription factor 20 (TCF20) can result in TCF20-associated neurodevelopmental disorder (TAND), a condition characterized by developmental delay and intellectual disability, autism, dysmorphisms, dystonia, and variable other neurological features. To date, a total of 91 individuals with TAND have been reported; ~67% of cases arose de novo, while ~10% were inherited, and, intriguingly, ~8% were either confirmed or suspected to have arisen via germline mosaicism. Here, we describe two siblings with a developmental condition characterized by intellectual disability, autism, a circadian rhythm sleep disorder, and attention deficit hyperactivity disorder (ADHD) caused by a novel heterozygous single nucleotide deletion in the TCF20 gene, NM_001378418.1:c.4737del; NP_001365347.1:p.Lys1579Asnfs*36 (GRCh38/hg38). The variant was not detected in DNA extracted from peripheral blood in either parent by Sanger sequencing of PCR-generated amplicons, or by deep sequencing of PCR amplicons using MiSeq and MinION. However, droplet digital PCR (ddPCR) of DNA derived from early morning urine detected the variation in 3.2% of the father’s urothelial cells, confirming germline mosaicism. This report is only the second to confirm with physical evidence TCF20 germline mosaicism and discusses germline mosaicism as a likely under-detected mode of inheritance in neurodevelopmental conditions.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"215-222"},"PeriodicalIF":2.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-025-01323-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515658","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}